Liposphere delivery systems for local anesthetics

{
  "publication_number": "US5227165A",
  "country": "US",
  "kind": "A",
  "title": "Liposphere delivery systems for local anesthetics",
  "abstract": "A local anesthetic microsuspension system is disclosed that includes lipospheres, that are solid, water-insoluble microparticles that have a layer of a phospholipid embedded on their surface. The core of the liposphere is a solid anesthetic such as lidocaine or marcaine, or an anesthetic dispersed in an inert solid vehicle, such as a wax. Anesthetic lipospheres provide a controlled delivery of local anesthetics to achieve extended, effective relief from pain by slowly releasing the anesthetic from the solid hydrophobic core. This is highly preferred over the situation in which an aqueous solution of local anesthetic must be frequently administered because it is quickly systemically absorbed.",
  "claims": [
    "1. A liposphere comprising: a core formed of a hydrophobic material existing as a solid at a temperature of 30° C. having anesthetic activity as a result of an anesthetic compound, and a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the liposphere, the combination forming a spherical structure having an average particle diameter between 0.35 and 250 microns, wherein the core may contain a vehicle for the anesthetic compound, and the anesthetic compound, vehicle, and phospholipid coating are in a ratio of anesthetic compound to vehicle to phospholipid between 1:0:0.01 and 1:100:100.",
    "2. The liposphere of claim 1, wherein the anesthetic activity is produced by a local anesthetic compound.",
    "3. The liposphere of claim 2 wherein the local anesthetic is selected from the group consisting of marcaine, procaine, chloroprocaine, cocaine, lidocaine, tetracaine, mepivacaine, etidocaine, bupivacaine, dibucaine, prilocaine, benzoxinate, proparacaine, benzocaine, butamben, and combinations thereof.",
    "4. The liposphere of claim 1 wherein the solid core comprises an anesthetic compound in a solid inert vehicle.",
    "5. The liposphere of claim 1 wherein the solid core has a melting point between 30° C. and 120° C.",
    "6. The liposphere of claim 4 wherein the vehicle is selected from the group consisting of natural and synthetic waxes, fatty acid esters, fatty alcohols, solid hydrogenated plant oils, tristearin, and biodegradable natural and synthetic polymers.",
    "7. The liposphere of claim 1 wherein the anesthetic activity is produced by a compound selected from the group consisting of halothane, isoflurane, enflurane, and methoxyflurane.",
    "8. The liposphere of claim 1 in a pharmaceutically acceptable carrier for enteral administration to a patient.",
    "9. The liposphere of claim 1 wherein the liposphere is in a pharmaceutically acceptable carrier for topical administration to a patient.",
    "10. The liposphere of claim 1 in a pharmaceutically acceptable carrier for parenteral administration to a patient.",
    "11. The liposphere of claim 1, further comprising a preservative.",
    "12. The liposphere of claim 1 further comprising a pharmaceutically active agent selected from the group consisting of antibiotics, antifungals, antivirals, chemotherapeutic agents and combinations thereof.",
    "13. A method of inducing local anesthesia comprising administering to a patient lipospheres comprising: a core formed of a hydrophobic material existing as a solid at 30° C. having anesthetic activity as a result of an anesthetic compound, and a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the liposphere, the combination forming a spherical structure having an average particle diameter between 0.35 and 250 microns, wherein the core may contain a vehicle for the anesthetic compound, and the anesthetic compound, vehicle, and phospholipid coating are in a ratio of anesthetic compound to vehicle to phospholipid between 1:0:0.01 and 1:100:100 in a pharmaceutically acceptable carrier.",
    "14. The method of claim 13 wherein the anesthetic activity is produced by a local anesthetic compound.",
    "15. The method of claim 14 wherein the local anesthetic is selected from the group consisting marcaine, procaine, chloroprocaine, cocaine, lidocaine, tetracaine, mepivacaine, etidocaine, bupivacaine, dibucaine, prilocaine, benzoxinate, proparacaine, benzocaine, or butamben.",
    "16. The method of claim 13 wherein the solid core includes an anesthetic compound and a vehicle for the anesthetic compound, which in combination with the anesthetic compound exists as a solid at 30° C.",
    "17. The method of claim 13 wherein the solid core has a melting point between 30° C. and 120° C.",
    "18. The method of claim 16 wherein the vehicle is selected from the group consisting of natural and synthetic waxes, fatty acid esters, fatty alcohols, solid hydrogenated castor and vegetable oils, tristearin, and biodegradable polymer.",
    "19. The method of claim 13 wherein the anesthetic activity is produced by a compound selected from the group consisting of halothane, isoflurane, enflurane, and methoxyflurane.",
    "20. The method of claim 13 wherein the liposphere is administered parenterally to the patient.",
    "21. The method of claim 13 wherein the liposphere is administered topically in a pharmaceutically acceptable carrier for topical administration.",
    "22. The method of claim 13 wherein the liposphere is administered enterally to the patient.",
    "23. The method of claim 13, wherein the core further comprises a preservative.",
    "24. The method of claim 13 further comprising a pharmaceutically active agent selected from the group consisting of antibiotics, antifungals, antivirals, chemotherapeutic agents and combinations thereof.",
    "25. A method of making lipospheres formed of a core that is a hydrophobic material existing as a solid at a temperature of 30° C. and a phospholipid coating surrounding the core, wherein the hydrophobic ends of the phospholipid are embedded in the solid core and the hydrophilic ends of the phospholipid are exposed on the surface of the resulting spherical liposphere structure having an average particle diameter between 0.35 and 250 microns, comprising forming a liquid of the hydrophobic core material, adding phospholipid to the core material, adding an aqueous solution to the liquid core material and phospholipid mixture, and mixing the liquid core material and phospholipid until a suspension of lipospheres is formed.",
    "26. The method of claim 25 further comprising sonicating and cooling the liquid core material and phospholipid after mixing.",
    "27. The method of claim 25 wherein the liquid core material and phospholipid are heated during mixing to a temperature at which the core material melts.",
    "28. The method of claim 25 wherein the the liquid core material includes an organic solvent, further comprising evaporating the solvent while mixing the core material and phospholipid.",
    "29. The method of claim 28 wherein aqueous buffer is added to the core material-phospholipid mixture after evaporating the solvent and before mixing until a suspension of lipospheres is formed."
  ],
  "description_excerpt": "This application is a continuation of application Ser. No. 07/607,543, filed Nov. 8, 1990 now abandoned, which in turn was a continuation-in-part of Ser. No. 07/435,546, filed Nov. 13, 1989, now abandoned.\n\nThis invention is in the area of controlled delivery devices for the administration of anesthetics.\n\nProducts for the moderation of pain, referred to as analgesics, represent one of the largest markets targeted by pharmaceutical companies. In fact, the market for ethical analgesic products in the United States alone is estimated to reach three billion dollars in 1990 and rise to over four billion dollars by 1995.\n\nPharmaceutical analgesics include a variety of classes of drugs, such as general anesthetics, non-steroidal anti-inflammatories, and local anesthetics. General anesthetics reduce pain by producing a loss of consciousness. Local anesthetics cause a loss of sensation in a localized area of the body without a loss of consciousness. Non-steroidal anti-inflammatories may ameliorate the pain but do not cause a loss of sensation or consciousness.\n\nAmong the general anesthetics are centrally acting narcotics, including morphine, demerol, fentanyl and codeine. These drugs act through opiate receptors in the central nervous system. The major advantage of centrally acting narcotics is the production of profound widespread analgesia for severe pain. These opiates are administered internally, parenterally, or topically. Dosage forms are available that are effective for durations of from 4 to 12 hours.",
  "cpc": [
    "A61K 9/167",
    "A01N 25/26",
    "A61K 9/127",
    "A61K 9/145",
    "A61K 9/1617",
    "A61K 9/5015",
    "Y10T 428/2984",
    "Y10T 428/2989"
  ],
  "ipc": [
    "A01N 25/26",
    "A61K 9/127",
    "A61K 9/14",
    "A61K 9/16",
    "A61K 9/50"
  ],
  "assignees": [
    "Nova Pharmaceutical Corp"
  ],
  "inventors": [
    "Abraham J. Domb",
    "Manoj Maniar"
  ],
  "filing_date": "1992-01-22",
  "publication_date": "1993-07-13",
  "grant_date": "1993-07-13",
  "priority_date": "1989-11-13",
  "application_number": "US-82621892-A",
  "family_id": "27411881",
  "cited_by_count": 176,
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}