Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1277—Preparation processes; Proliposomes
  • A61K9/1278—Post-loading, e.g. by ion or pH gradient

Definitions

• the present invention is directed to a sustained-release pharmaceutical composition
• a sustained-release pharmaceutical composition comprising of a sedative drug with a high drug to lipid ratio and a high encapsulation efficiency using at least one trapping agent.
• the high drug to lipid ratio, high encapsulation efficiency and sustained release profile of the claimed pharmaceutical composition reduce the frequency of drug administration, increase patient compliance and improve the therapeutic outcome.
• Dexmedetomidine is a highly selective o ⁇ -adrenergic receptor agonist with analgesic and sedative properties without significant respiratory depression. It has been approved for treating anxiety and procedural sedation in humans and companion animals in many countries. This medication is typically administered as an intravenous or intramuscular injection, although a transdermal patch has been proposed (W02015054058A1).
• Liposomes have been widely used for developing sustained-release formulations for various drugs.
• Drug loading into liposomes can be attained either passively (the drug is encapsulated during liposome formation) or remotely /actively (creating a transmembrane pH- or ion-gradient during liposome formation and then the drug is loaded by the driving force generated from the gradients after liposome formation) (US Patent No. 5,192,549 and 5,939,096).
• US Patent No. 5,192,549 and 5,939,096 Although the general methods of drug loading into liposomes are well documented in the literature, only a handful of therapeutic agents were successfully loaded into liposomes with high drug to lipid ratio and high encapsulation efficiency, which are important to sustain the release of the encapsulated therapeutic agent.
• liposomes Numerous factors can affect the drug to lipid ratio and encapsulation efficiency of liposomes, including but not limited to, the physical and chemical properties of the therapeutic agent, for example, hydrophilic/hydrophobic characteristics, dissociation constant, solubility and partition coefficient, lipid composition, trapping agent, reaction solvent, and particle size (Proc. Natl. Acad. Sci U S A. 2014; 111(6): 2283-2288 and Drug Metab. Dispos. 2015; 43 (8): 1236-45).
• the physical and chemical properties of the therapeutic agent for example, hydrophilic/hydrophobic characteristics, dissociation constant, solubility and partition coefficient, lipid composition, trapping agent, reaction solvent, and particle size
• a sustained release pharmaceutical composition comprises (a) at least one first liposome comprising a bilayer membrane; (b) a trapping agent; and (c) a sedative drug, wherein the bilayer membrane comprises at least one lipid and the molar ratio of the drug to the lipid is equal to or higher than about 0.02 is provided.
• methods for sedating a subject, comprising the steps of administering the pharmaceutical composition described herein to a subject in need thereof.
• methods for treating pain in a subject, comprising the steps of administering (a) the pharmaceutical composition described herein and (b) an anesthetic, an analgesic or a combination thereof to a subject in need thereof.
• a medicament for sedating a subject or treating pain in a subject comprising a therapeutically effective amount of the pharmaceutical composition described herein.
• FIG. 1A and FIG. 1B are line graphs showing the release profiles of liposomal dexmedetomidine and free dexmedetomidine (dexmedetomidine) in plasma free environment (FIG. 1A) and in human plasma (FIG. 1B).
• FIG. 2 is a line graph showing the plasma dexmedetomidine concentration in rats after intramuscular injection of liposomal dexmedetomidine and free dexmedetomidine.
• FIG. 3A illustrates schematically the four injections administered to the back of the guinea pig.
• FIG. 3B is a line graph showing the non-response rate of guinea pigs to pain stimulus after intracutaneous injection of (a) free ropivacaine, (b) free ropivacaine plus liposomal dexmedetomidine (L-DEX), (c) liposomal ropivacaine composition or (d) liposomal ropivacaine composition plus L-DEX.
• L-DEX liposomal dexmedetomidine
• FIG. 4A illustrates schematically the intramuscular injection sites (A and B) and the intracutaneous injection sites (C and D) of Group A and Group B guinea pigs.
• FIG. 4B is a line graph showing the effect of saline or liposomal dexmedetomidine administered outside the pin prick area of guinea pigs with the free ropivacaine or liposomal ropivacaine composition administered inside the pin prick area of the guinea pigs.
• an “effective amount,” as used herein, refers to a dose of the pharmaceutical composition to sedate a subject or to treat pain in combination with an anesthetic and/or an analgesic to decrease the dosing frequency or dose of the anesthetic or analgesic.
• the term “effective amount” and“therapeutically effective amount” are used interchangeably.
• the term“treating,”“treated,” or“treatment,” as used herein, includes preventative (e.g. prophylactic), palliative, and curative methods, uses or results.
• the terms“treatment” or “treatments” can also refer to compositions or medicaments.
• the term “treating” encompasses provide sedation or reduce or complete amelioration of the symptoms or signs of anxiety.
• the term“treating” encompasses reducing or delaying one or more symptoms or signs of pain or the complete amelioration of pain as detected by art-known techniques, such as pain score.
• the reduction of pain can be about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between.
• adjuvant involves the use of the pharmaceutical compositions or medicaments described herein as adjuvants to enhance the effect of an anesthetic or analgesic and/or reduce the anesthetic or analgesic requirements.
• anesthetic including but not limited to, general anesthetics such as induction agents (e.g., ketamine, propofol and thiopentone), muscle relaxants (e.g., atracurium, pancuronium, rocuronium, suxamethonium and vecuronium), inhalational anaesthetics (e.g., desflurane, enflurane, isoflurane and sevoflurane), regional anesthetics such as ropivacaine, levobupivacaine and bupivacaine, local anesthetics such as ropivacaine, lidocaine and bupivacaine.
• analgesic include opioid analgesic such as morphine, fentanyl, and codeine or non-opioid analgesic such as non-steroidal anti-inflammatory drug (NSAID) and paracetamol.
• NSAID non-steroidal anti-inflammatory drug
• subject can refer to a vertebrate requiring sedation or treatment of anxiety or pain or to a vertebrate deemed to be in need of sedation or treatment of anxiety or pain.
• Subjects include all warm-blooded animals, such as mammals, such as a primate, and, more preferably, a human. Non-human primates are subjects as well.
• the term subject includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.) and laboratory animals (for example, mouse, rabbit, rat, gerbil, guinea pig, etc.).
• livestock for example, cattle, horses, pigs, sheep, goats, etc.
• laboratory animals for example, mouse, rabbit, rat, gerbil, guinea pig, etc.
• the terms“liposome,”“liposomal” and related terms as used herein are characterized by an interior aqueous space sequestered from an outer medium by one or more bilayer membranes forming a vesicle.
• the interior aqueous space of the liposome is substantially free of a neutral lipid, such as triglyceride, non-aqueous phase (oil phase), water-oil emulsions, a second liposome or other mixtures containing non-aqueous phase.
• Non-limiting examples of liposomes include small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), and multi-lamellar vesicles (MLV) with an average diameter ranges from 50-20 qm, 50-450 nm, 50-400 nm, 50-350 nm, 50-300 nm, 50-250 nm, 50-200 nm, 100-500 nm, 100-450 nm, 100-400 nm, 100-350 nm, 100-300 nm, 100-250 nm or 100-200 nm.
• SUV small unilamellar vesicles
• LUV large unilamellar vesicles
• MLV multi-lamellar vesicles
• Bilayer membranes of liposomes are typically formed by at least one lipid, i.e. amphiphilic molecules of synthetic or natural origin that comprise spatially separated hydrophobic and hydrophilic domains.
• lipid including but not limited to, dialiphatic chain lipids, such as phospholipids, diglycerides, dialiphatic glycolipids, single lipids such as sphingomyelin and glycosphingolipid, and combinations thereof.
• Examples of phospholipid according to the present disclosure include, but not limited to, 1 ,2-dilauroyl-,v/7- glycero-3-phosphocholine (DLPC), 1 ,2-dimyristoyl-.s77-glycero-3-phosphocholine (DMPC),
• DPPC 1.2-dipalmitoyl-.s77-glycero-3-phosphocholine
• PSPC 1 -palmitoyl-2-stearoyl-,s77-glycero-3- phosphocholine
• POPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-sn-glycero-S -phosphocholine
• DOPC 1,2- distearoyl-s
• the mole percent of the lipid in the bilayer membrane of the first liposome is about 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45 or any value or range of values therebetween (e.g., about 45-85%, about 45-80%, about 45-75%, about 45- 70%, about 45-65%, about 50-85%, about 50-80%, about 50-75%, about 50-70% or about 50-
• the lipid of the bilayer membrane of the first liposome comprises a mixture of a first lipid and a second lipid.
• the first lipid is selected from the group consisting essentially of phosphatidylcholine (PC), HSPC, DSPC, DPPC, DMPC, PSPC and combination thereof and the second lipid is selected from the group consisting essentially of a phosphatidylethanolamine, phosphatidylglycerol, PEG-DSPE, DPPG and combination thereof.
• the mole percent of the first lipid in the bilayer membrane is about 84.9, 84.5, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71,
• the mole percent of the second lipid in the bilayer membrane is about 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.5, 0.1 or any value or range of values therebetween (e.g., about 0.1-25% or about 0.5-25%).
• the bilayer membrane of the liposome further comprises less than about 55 mole percentage of steroids, preferably cholesterol.
• the mole % of steroid, such as cholesterol, in the bilayer membrane is about 15-55%, about 20-55%, about 25-55%, about 15-50%, about 20-50%, about 25-50%, about 15-45%, about 20-45%, about 25-45%, about 15-40%, about 20-40% or about 25-40%.
• the mole % of the lipid and cholesterol in the bilayer membrane of the first liposome is about 45-85%: 15-55% or about 50-80%: 20-50%.
• the mole % of the first lipid, the second lipid and cholesterol in the bilayer membrane of the first liposome is about 40-84.9%: 0.l%-25%: 15-55%, 40-75%: 0.1- 25%: 20-50% or 40-70%: 0.1-25%: 25-50% and the first lipid is HSPC, DMPC, DSPC or combination thereof and the second lipid is DSPE-PEG2000, DPPG or combination thereof.
• the term“remote loading” as used herein is a drug loading method which involves a procedure to transfer drugs from the external medium across the bilayer membrane of the liposome to the interior aqueous space by a polyatomic ion-gradient.
• Such gradient is generated by encapsulating at least one polyatomic ion as a trapping agent in the interior aqueous space of the liposome and replacing the outer medium of the liposome with an external medium with a lower polyatomic ion concentration, for example, pure water, sucrose solution and saline, by known techniques, such as column separation, dialysis or centrifugation.
• a polyatomic ion gradient is created between the interior aqueous space and the external medium of the liposomes to trap the therapeutic agent in the interior aqueous space of the liposomes.
• Exemplary polyatomic ion as trapping agents include, but are not limited to, sulfate, sulfite, phosphate, hydrogen phosphate, molybdate, carbonate and nitrate.
• Exemplary trapping agents include, but are not limited to, ammonium sulfate, ammonium phosphate, ammonium molybdate, ammonium sucrose octasulfate, triethylammonium sucrose octasulfate and dextran sulfate.
• the concentration of ammonium sulfate is about 100 to about 600 mM, about 150 to about 500 mM or about 200 to about 400 mM.
• the concentration of triethylammonium sucrose octasulfate is about 10 to about 200 mM or about 50 to about 150 mM.
• the concentration of ammonium phosphate is about 100 to about 600 mM, about 150 to about 500 mM or about 200 to about 400 mM.
• the concentration of dextran sulfate is about 0.1 to 20 mM or about 1 to 10 mM.
• the liposomes can be prepared by any of the techniques now known or subsequently developed.
• the MLV liposomes can be directly formed by a hydrated lipid film, spray-dried powder or lyophilized cake of selected lipid compositions with trapping agent;
• the SUV liposomes and LUV liposomes can be sized from MLV liposomes by sonication, homogenization, microfluidization or extrusion.
• the present invention is directed to a sustained release pharmaceutical composition, comprising (a) at least one first liposome comprising a bilayer membrane; (b) a trapping agent; and (c) a sedative drug, wherein the bilayer membrane comprises at least one lipid and the molar ratio of the drug to the lipid is above or equal to 0.02.
• the sustained release pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, diluent, vehicle, carrier, medium for the active ingredient, a preservative, cryoprotectant or a combination thereof.
• the weight percent of the bilayer membrane in the pharmaceutical composition is about 0.1-12%; the weight percent of the trapping agent in the pharmaceutical composition is about 0.1-10%; and the weight percent of the pharmaceutically acceptable excipient (such as sucrose, histidine, sodium chloride and ultrapure water), diluent, vehicle, carrier, medium for the active ingredient, a preservative, cryoprotectant or a combination thereof in the pharmaceutical composition is about 80.0-99.9%.
• the sedative drug is an alpha-2-adrenoceptor (oc 2 ) agonist.
• a 2 agonist include clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, guanfacine, medetomidine, methyldopa, methylnorepinephrine, tizanidine, xylazine and dexmedetomidine.
• the sustained release profile of the pharmaceutical composition prolongs the half-life and the therapeutic efficacy by maintaining the therapeutic concentration of the sedative drug, and hence, reduces the dosage and/or the frequency of sedative drug administration ⁇
• the sustained release profile of the pharmaceutical composition enhances the effect of the co-administered anesthesia or analgesic agent and reduces the dosage and/or the frequency of administration of co-administered anesthesia or analgesic agent.
• the sustained release profile of the pharmaceutical composition is owed to a drug encapsulation efficiency of at least 40%, 50%, 55%, 60%, 65%, 70% or 75%.
• sustained release profile of the pharmaceutical composition is due to the higher drug to lipid molar ratio.
• the molar ratio of the sedative drug to the one or more lipids is above or equal to 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08 or 0.09, alternatively from 0.02 to 10, from 0.02 to 5, from 0.02 to 2, from 0.02 to 1, from 0.05 to 10, from 0.05 to 5, from 0.05 to 2, from 0.05 to 1, from 0.05 to 0.5, from 0.09 to 10, from 0.09 to 5, from 0.09 to 2, from 0.09 to 1 or from 0.09 to 0.5.
• the half-life of the sedative drug is extended by at least 2-fold compared to that of the free sedative drug.
• the pharmaceutical composition further comprises an analgesic, an anesthetic or the combination thereof.
• the analgesic, the anesthetic or the combination thereof is not encapsulated in a liposome.
• the analgesic, the anesthetic or the combination thereof is encapsulated in a second liposome.
• the second liposome is a multilamellar vesicle disclosed in PCT/US 18/48329, the content of which is incorporated herein in its entirety.
• the second liposome comprises at least one lipid and cholesterol at a molar ratio of from 1:0.01 to 1:1.
• the term“encapsulated” and“entrapped” are used interchangeably.
• the invention also provides methods to sedate a subject, comprise the step of administration of an effective amount of the pharmaceutical composition as described herein to the subject in need thereof.
• the invention further provides methods to reduce or treat pain, by administering (a) an effective amount of the pharmaceutical composition as described herein and (b) an analgesic, an anesthetic or the combination thereof to a subject in need thereof, whereby the pain is reduced.
• the pharmaceutical composition enhances and sustains the effect of the analgesic, the anesthetic or the combination thereof, so the dose and the administering frequency of the analgesic or anesthetic can be reduced while the subject has a longer pain-free period compared to using the anesthetic or analgesic in monotherapy regimen.
• the pharmaceutical composition can be administered before, after or simultaneously with the anesthetic or analgesic.
• the pharmaceutical composition is formulated to be suitable for cutaneous injection, such as subcutaneous, subdermal, transdermal, intradermal or intramuscular route.
• the pharmaceutical composition is also formulated to be administered as a transdermal patch or administered by intravenous, oral or inhalation route.
• the dosage of the pharmaceutical composition of the present invention can be determined by the skilled person in the art according to the embodiments. Unit doses or multiple dose forms are contemplated, each offering advantages in certain clinical settings. According to the present invention, the actual amount of the pharmaceutical composition to be administered can vary in accordance with the age, weight, condition of the subject to be treated, any exiting medical conditions, and on the discretion of medical professionals.
• the pharmaceutical compositions disclosed herein significantly extended the release of the encapsulated therapeutic agent.
• the pharmaceutical composition of the present invention extended the half-life of intramuscularly (IM) administered dexmedetomidine to 4.07 hours in rats (as disclosed in Example 4) compared to the FDA approved dexmedetomidine formulation for IM injection (1.5 hours in rats, Precedex ® New Drug Application submitted package, Abbot Laboratories Corporation, Application No.: 21-038).
• IM intramuscularly
• the unencapsulated dexmedetomidine hydrochloride was separated by a SephadexTM G-50 Fine gel (GE Healthcare) or dialysis bag (Spectrum Labs) against a 9.4% sucrose solution to obtain the liposomal dexmedetomidine formulation.
• the concentrations of the encapsulated dexmedetomidine hydrochloride and the lipid of the liposomal dexmedetomidine formulation were measured using a HPLC and an ultraviolet/visible (UV/Vis) spectrophotometer and used to calculate the drug to lipid molar ratio (D/L) of the liposomal dexmedetomidine formulation.
• UV/Vis ultraviolet/visible
• the encapsulation efficiency was calculated by the drug to lipid molar ratio (D/L) of liposomal dexmedetomidine formulation compared to that of the nominal D/L of reaction mixture, which was calculated by dividing the concentration of dexmedetomidine by the lipid concentration of empty liposome.
• the particle size distribution was measured by a dynamic light scattering instrument (Zetasizer Nano-ZS90, Malvern).
• the liposomal dexmedetomidine formulation achieved a final D/L of 0.32 and an encapsulation efficiency of 76.6%.
• the mean diameter of the liposomes was 202.5 nm.
• the liposome formulations were prepared according to Example 1 , with the following trapping agents: (1) 75 mM of triethylammonium sucrose octasulfate, (2) 300 mM of ammonium sulfate, (3) 200 mM ammonium phosphate and (4) 7.0 mM of dextran sulfate. Table 1 shows the effect of different trapping agents on drug loading.
• 0.2 mL of liposomal dexmedetomidine formulation prepared according to Example 1 and 0.2 mL of free dexmedetomidine hydrochloride were placed in separate dialysis bags, each containing 0.8 mL of human plasma (Valley Biomedical, Inc.) and both ends of dialysis bags were sealed.
• Each dialysis bag was immersed in 20 mL of PBS at pH 7.4 in a 50-mL centrifuge tube and incubated at 37 ⁇ 1 °C water bath for 168 or 72 hours.
• the rats were divided into two groups (n - 4 in each group), one group received intramuscular (IM) injection of 100 mg/kg of free dexmedetomidine hydrochloride, prepared by dissolving the dexmedetomidine hydrochloride in 9.4% sucrose solution with a final concentration of 250 mg/mL.
• the other group received IM injection of 106 mg/kg of liposomal dexmedetomidine hydrochloride, prepared according to Example 1.
• Blood samples were collected at 15, 30 min, 1, 2, 4, 8, 24, 48, and 72 hours post- injection. Plasma samples were obtained by centrifugation, kept frozen at -80°C and analyzed using liquid chromatography- tandem mass spectrometry.
• the plasma concentrations versus time curves were analyzed using a noncompartmental analysis model in PKSolver (Comput. Methods Programs Biomed. 2010;99(3):306-314).
• the PK parameters of the two dexmedetomidine formulations are summarized in Table 2.
• FIG. 2 shows dexmedetomidine was undetectable in the plasma of rats 8- hour post IM injection of free dexmedetomidine whereas dexmedetomidine was detected in the plasma of rats 24-hour post IM injection of liposomal dexmedetomidine formulation.
• the results support a conclusion that the claimed pharmaceutical composition sustained the release of dexmedetomidine.
• the 4 formulations are: (A) 1.5 mg of free ropivacaine, prepared by dissolving ropivacaine hydrochloride monohydrate (Focus Synthesis) in 9.4% sucrose solution at 18.0 mg/mL, (B) 1.5 mg of free ropivacaine and 0.2 mg of liposomal dexmedetomidine formulation prepared according to Example 1, (C) 1.5 mg of liposomal ropivacaine composition and (D) 1.5 mg of liposomal ropivacaine composition and 0.2 mg of liposomal dexmedetomidine formulation prepared according to Example 1.
• the liposomal ropivacaine composition was disclosed in PCT/US 18/48329.
• the anesthesia effect of ropivacaine was assessed at 30 minutes (0.5 hour), 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 10 and 24 hours post- injection.
• the anesthetic effect was determined by observing the guinea pig’s response to stimuli around individual wheals (pin prick test).
• PD data obtained from the pin prick tests were analyzed using an inhibitory effect sigmoid E max model in PKSolver (Comput Methods Programs Biomed. 2010;99(3):306-314).
• the PD parameters of the ropivacaine with and without the L- DEX are summarized in Table 3Table 3 .
• FIG. 3B shows the duration of anesthesia induced by free ropivacaine or liposomal ropivacaine composition was extended with the co-administration of L-DEX.
• the results support a conclusion that the claimed pharmaceutical composition is an effective adjuvant of an anesthetic.
• guinea pigs were used in this study and was divided into two groups (Groups A and B). As illustrated in FIG. 4A, the guinea pigs in Group B (n - 2) received an intramuscular injection of 2.0 pg/kg of L-DEX prepared according to Example 1 in its left dorsal flank (site B of FIG. 4A, outside the pin prick testing area) and the guinea pigs in Group A (n - 2) received a intramuscular saline injection in its left dorsal flank (site A of FIG. 4A, outside the pin prick testing area). Each guinea pig in Group A and Group B received 4 intracutaneous injections on its back.
• the anesthetic effect of ropivacaine was assessed at 30 minutes (0.5 hour), 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0 and 10 hours post-injection.
• the anesthetic effect was determined by observing the guinea pig’s response to stimuli around individual wheals (i.e., pin prick test). PD data obtained from the pin prick tests was analyzed using an inhibitory effect sigmoid E max model in PKSolver (Comput Methods Programs Biomed.
• the PD parameters of the free ropivacaine and liposomal ropivacaine composition with or without the liposomal dexmedetomidine formulation are summarized in Table 4. [0069] The results in Table 4 show the administration of L-DEX increased TE 50 of free ropivacaine and liposomal ropivacaine composition and extended the duration of anesthetic effect of free ropivacaine and liposomal ropivacaine composition by about 1.1- to 1.6-times.
• Table 4 PD parameters derived from guinea pigs receiving intracutaneous injections of free ropivacaine and liposomal ropivacaine composition with or without L-DEX.
• FIG. 4B shows the duration of the anesthetic effect of ropivacaine was extended even with the distant delivery (i.e., delivery outside the pin prick testing area) of liposomal dexmedetomidine formulation.
• the results support a conclusion that the claimed pharmaceutical composition is an effective adjuvant of an anesthetic.

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