WO2020211762A1 - 脂性药物制剂及其应用 - Google Patents

脂性药物制剂及其应用 Download PDF

Info

Publication number
WO2020211762A1
WO2020211762A1 PCT/CN2020/084832 CN2020084832W WO2020211762A1 WO 2020211762 A1 WO2020211762 A1 WO 2020211762A1 CN 2020084832 W CN2020084832 W CN 2020084832W WO 2020211762 A1 WO2020211762 A1 WO 2020211762A1
Authority
WO
WIPO (PCT)
Prior art keywords
lipid
lipid drug
drug preparation
mass percentage
preparation
Prior art date
Application number
PCT/CN2020/084832
Other languages
English (en)
French (fr)
Inventor
张洁
唐培克
Original Assignee
湖州依诺唯新药物制剂有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 湖州依诺唯新药物制剂有限公司 filed Critical 湖州依诺唯新药物制剂有限公司
Priority to US17/603,015 priority Critical patent/US20220193014A1/en
Priority to EP20792218.8A priority patent/EP3957328A4/en
Priority to CN202080021973.7A priority patent/CN113597316B/zh
Publication of WO2020211762A1 publication Critical patent/WO2020211762A1/zh

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to a lipid drug preparation and its application.
  • Local anesthetic preparations are used to prevent or treat skin or mucous membrane pain, for example: 2% lidocaine hydrochloride gel is used to relieve pain related to sunburn; Enna (English name EMLA) is a kind of lidocaine An emulsion of low-point eutectic oil drops with prilocaine, which is used for anesthesia of intact skin before surgery with pain; Lidoderm is a solidified gel patch containing 5% lidocaine, which is used to relieve banding Postherpetic neuralgia (the skin itself is intact); Pliaglis is an emulsion containing 7% lidocaine and 7% tetracaine low-point eutectic oil drop-shaped emulsion, which is used for painful intact skin before surgery Anesthesia.
  • each of the above-mentioned local anesthetic preparations has serious limitations.
  • Lidocaine hydrochloride gel cannot anesthetize intact skin
  • prilocaine in EMLA can cause methemoglobinemia
  • tetracaine in Pliaglis can cause allergic reactions related to ester local anesthetics
  • tetracaine can It is hydrolyzed, so Pliaglis must be stored in refrigeration to reduce the rate of hydrolysis
  • Lidoderm cannot anesthetize complete skin within 120 minutes or even 4 hours, and Lidoderm cannot be used for more than 12 hours each time.
  • the common limitation of the above-mentioned local anesthetic preparations is that they cannot achieve long-term continuous and safe analgesic effects.
  • the ideal product can have 6, 12, 18, 24, 30, or even 48 hours or longer continuous analgesic effect. Therefore, seeking a safe, long-term and continuous safe analgesic effect is a problem that needs to be solved urgently.
  • Human tissue surfaces that are not covered by skin or mucous membranes, such as surgical incisions, burn surfaces, wound surfaces, etc. These open human body surfaces often require analgesia.
  • the open human body surface is characterized by the absorption of foreign substances, such as local anesthetics. There are no barriers like skin.
  • open human body surface or “open human tissue surface” refers to the surface of human tissue without skin or mucous membranes or the human body covered by incomplete skin or mucous membranes (such as broken skin or mucous membranes) Tissue surface, including sutured and unsutured surgical incision wounds) Therefore, if a local anesthetic preparation without sustained-release function is placed on an open human surface, for example, 2% lidocaine hydrochloride commonly used in hospitals is applied For burns and scalds on the surface, the local anesthetic contained in the preparation will be quickly absorbed into the systemic blood circulation, resulting in a high blood concentration that may cause serious side effects and a short duration of analgesic effect. Drug formulations with sustained-release effects are also a problem that needs to be solved urgently.
  • Incisional analgesia after surgery is a common requirement.
  • the commonly used method is to use analgesic pumps to transfer drugs that act on the central nervous system, such as fentanyl and dolanidine, into the patient's body.
  • These drugs enter the brain tissue after passing through the blood-brain barrier and bind to related pain receptors to achieve the purpose of analgesia.
  • all these central nervous system analgesics may cause serious side effects, such as respiratory depression and addiction. Therefore, the use of local anesthetics without central nervous function to control postoperative incision pain would be a significant improvement.
  • the local anesthetic preparation for surgical incision pain relief must release the local anesthetic contained in it in a slow-release manner.
  • the product Exparel recently launched by Pacira Pharmaceuticals, Inc. uses a specially formulated local anesthetic, bupivacaine, to replace or reduce the amount of central nerve analgesics, which has been welcomed by doctors and patients.
  • Exparel has many weaknesses: (1) The liposomes encapsulating bupivacaine in the preparation are unstable, so Exparel must be stored and transported under refrigeration; (2) Exparel must be injected with up to 20 needles along the surgical incision. It is very inconvenient and time-consuming to use; (3) The need for analgesia after surgery is generally at least 2-3 days, but the effective analgesic effect of Exparel is only 24 hours. Therefore, it is also an urgent problem to find a pharmaceutical preparation that can achieve analgesia of incisions after long-term surgery, can be conveniently used, and can be transported and stored at room temperature.
  • the technical problem to be solved by the present invention is to overcome the defect that the local anesthetic preparation in the prior art cannot achieve long-term continuous and safe analgesic effect, and to provide a new type of lipid drug preparation and its application.
  • the lipidic pharmaceutical preparation of the present invention is mainly applied to the open human body surface that needs analgesia, can take effect in a short time, and can obtain 12, 24, 36, 48, 72 hours, or even longer continuous analgesic effects .
  • the lipid drug preparation of the present invention can provide safe, long-term and effective analgesia.
  • the analgesic effect refers to a statistically significant analgesic effect compared with a placebo without an analgesic component. Compared with placebo, the analgesic effect can be measured by the internationally accepted Visual Analog Scale and other pain test methods.
  • the lipid drug preparation of the present invention also has the advantages of room temperature storage and convenient use.
  • the lipid drug preparation of the present invention can replace the traditional central nervous system anesthetics, thereby avoiding the serious problems caused by central nervous system anesthetics. side effect.
  • the present invention provides a lipid drug preparation
  • the lipid drug preparation includes a local anesthetic and a lipid substance
  • the mass percentage of the local anesthetic in the lipid drug preparation is 2%-50%
  • the mass percentage of the lipid substance in the lipid drug preparation is 30%-98%; the mass percentage of each component in the lipid drug preparation The sum is 100%.
  • the mass percentage of the local anesthetic in the lipid drug preparation is preferably 3%-50%, 10%-50%, 20%-50%, 6%-50%, 6 %-40%, 7%-35%, 8%-30%, 8%-24%, 10%-24%, or 3%-8%, such as about 18%, about 25%, 18% or 25 %.
  • the local anesthetic is preferably lidocaine, bupivacaine or tetracaine, and more preferably lidocaine.
  • the mass percentage of the lipid substance in the lipid drug preparation is preferably 50%-98%, more preferably 55%-84%.
  • the melting temperature of the lipid drug formulation is preferably 37°C or higher, more preferably 45°C or higher, still more preferably 45-200°C, and still more preferably 45-80°C .
  • the lipid pharmaceutical preparations within the melting temperature range mentioned above will not become a free-flowing liquid after being put into human tissues, thereby better achieving the effect of sustained release.
  • the melting temperature of the lipid drug formulation may also be 25-36°C, or 15-33°C.
  • the lipid pharmaceutical preparations within the melting temperature range can become viscous but flowable liquid after being applied to the surface of human tissues, so that it is easier to reach the surface of human tissues that need analgesia. This is very important in certain analgesic applications. For example, wounds in the anus and/or colon close to the anus after anorectal surgery are often very painful.
  • the fluidity of the lipid pharmaceutical preparation can make it contact all the surfaces inside and outside the anus that need to be analgesic Or incision.
  • the lipid drug preparation may also contain a bacteriostatic component; the bacteriostatic component is preferably one or more of chlorhexidine, antibiotics and sulfa drugs, more preferably chlorhexidine set.
  • the quality of the chlorhexidine in the lipid drug preparation is preferably 0.1% to 5%, more preferably 0.2% to 2%.
  • the lipid drug preparation may also contain water-soluble substances.
  • the water-soluble substance may be glycerin, for example.
  • the mass percentage of the water-soluble substance in the lipid drug preparation is preferably 8%-12%.
  • the lipid drug preparation may also contain chitin and/or chitin derivatives.
  • the chitin derivative is preferably carboxylated chitosan.
  • the mass percentage of the carboxylated chitosan in the lipid drug preparation is preferably 3% to 5%.
  • the above lipid pharmaceutical preparations containing chitin and/or chitin derivatives have higher hardness and certain antibacterial ability.
  • the lipid drug preparation may also contain acid or sodium sulfate.
  • the mass percentage of the acid or sodium sulfate in the fatty pharmaceutical preparation is preferably 4%-8%.
  • the acid may be an uncrosslinked acid or a crosslinked acid.
  • the sodium hydrochloride may be uncrosslinked sodium hydrochloride or crosslinked sodium hydrochloride.
  • the above-mentioned lipid pharmaceutical preparations containing acid or sodium sulfate can form a gel after contacting and absorbing body fluids.
  • the lipid drug preparation may also contain a pH buffer pair.
  • the mass percentage of the pH buffering pair in the lipid drug formulation is preferably 4-18%, for example 12%.
  • the pH buffer pair is preferably a pH buffer pair composed of disodium hydrogen phosphate and sodium dihydrogen phosphate, a pH buffer pair composed of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and a pH buffer composed of sodium tetraborate and sodium hydroxide Or a pH buffer pair composed of tris and HCl, more preferably a pH buffer pair composed of disodium hydrogen phosphate and sodium dihydrogen phosphate or a pH buffer pair composed of sodium tetraborate and sodium hydroxide, and further It is preferably a pH buffer pair composed of disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • the lipid substance may be a lipid substance conventionally used in the art, and usually refers to one or more of animal fat, vegetable fat, and other fatty substances.
  • the other fatty substances Refers to medicinal or edible fats other than animal fat and vegetable fat approved by the Food and Drug Administration of China, the United States, or other countries.
  • the animal fat is preferably lecithin and/or cholesterol.
  • the vegetable fat is preferably soybean phospholipid, sunflower seed phospholipid or vegetable oil; the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C.
  • the vegetable oil is more preferably soybean oil.
  • the lipid substance is a combination of phospholipid and vegetable oil, more preferably a combination of lecithin and vegetable oil or a combination of lecithin and soybean oil. More preferably, the mass percentage of the phospholipid in the lipid drug formulation is 40%-80%, and the mass percentage of the soybean oil in the lipid drug formulation is 8%-50%.
  • the phospholipids refer to phospholipids extracted from any raw material, including lecithin, soybean phospholipids, sunflower seed phospholipids, and phospholipids from other sources.
  • the lipid drug preparation includes the following components (or composed of the following components by mass percentage): 3%-50% lidocaine, 30%-90% % Phospholipid (for example, lecithin) and 3%-20% vegetable oil.
  • the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C.
  • the vegetable oil is more preferably soybean oil.
  • the lipid drug formulation includes the following components (or composed of the following components by mass percentage): 5%-50% lidocaine, 40%-85% % Phospholipid (for example, lecithin) and 3%-20% vegetable oil.
  • the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C.
  • the vegetable oil is more preferably soybean oil.
  • the lipid drug formulation includes the following components (or composed of the following components by mass percentage): 15%-25% lidocaine, 65%-85% % Phospholipids and 6%-15% vegetable oil.
  • the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C.
  • the vegetable oil is more preferably soybean oil.
  • the lipid drug preparation includes the following components (or composed of the following components by mass percentage): 3%-8% lidocaine, 40%-70% % Phospholipid (for example, lecithin) and 25%-55% vegetable oil.
  • the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C.
  • the vegetable oil is more preferably soybean oil.
  • the lipid drug preparation may also contain 8-12% glycerin by mass percentage.
  • the lipid drug preparation may also contain 3%-5% (for example, 4%) of carboxylated chitosan by mass.
  • the lipid drug preparation may also contain 4%-8% sodium sulfate by mass.
  • the lipid drug preparation includes the following mass percentages of each component (or consists of the following mass percentages of each component): 5%-30% (for example, 20%) of Lido Caine, 55%-85% (for example, 72%) phospholipid (for example, lecithin), and 8%-15% (for example, 8%) of sodium sulfate.
  • the present invention also provides a lipid drug preparation, the lipid drug preparation comprising lidocaine and auxiliary materials, the mass percentage of the lidocaine in the lipid drug preparation is 3%-50%, preferably 14% -50%, more preferably 15%-50%, the excipients are excipients that can be safely absorbed by the human body, and the excipients also contain lipid substances, the quality of the lipid substances in the lipid drug preparation The percentage is more than 30% and not 100%; the sum of the mass percentages of the components in the lipid drug preparation is 100%;
  • the lidocaine in the lipid drug preparation can be released from the lipid drug preparation to the contact with the lipid drug preparation in a slow-release manner
  • the surface of the human tissue and can make the patient's average blood concentration peak at the maximum dose not higher than 5000ng/mL, preferably not higher than 2500ng/mL, (for example, it may not be higher than 2000ng/mL),
  • the effective analgesic time is not shorter than 24 hours; wherein, the maximum dose is 0.5 g of the lipid drug preparation/kg body weight.
  • the excipients are preferably those in pharmaceutical preparations that have been approved for sale by the Food and Drug Administration of China, the United States, or other countries.
  • the effective analgesic time is not shorter than 48 hours.
  • the lipid material is one or more of animal fat, vegetable fat and other fatty material, and the other fatty material refers to China, the United States, or other countries Medicinal or edible fatty substances other than animal fat and vegetable fat approved by the Food and Drug Administration.
  • the animal fat is preferably lecithin and/or cholesterol.
  • the vegetable fat is preferably soybean lecithin, sunflower seed lecithin or vegetable oil; the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C; the vegetable oil is more preferably The best place is soybean oil.
  • the lipid substance is preferably a combination of phospholipid and vegetable oil, more preferably a combination of lecithin and vegetable oil or a combination of lecithin and soybean oil.
  • the lipidic pharmaceutical preparations are not stratified under high temperature sterilization conditions, and the temperature of the high temperature sterilization conditions is 121°C or higher, for example, 121°C.
  • the high temperature sterilization conditions The high temperature sterilization conditions
  • the time is 15 minutes or more; for example, it can be 15 minutes.
  • the lipid drug preparation includes the following components (or consists of the following components): lidocaine, phospholipids (such as lecithin) and soybean oil, and the lidocaine is
  • the mass percentage of the lipid drug preparation is 3%-25%, and the mass percentage of the phospholipid (for example, lecithin) in the lipid drug preparation is 50%-85% or 50%-77%.
  • the mass percentage of soybean oil in the fatty pharmaceutical preparation is 6%-50%, 6%-45%, 7%-25% or 4%-25%.
  • the mass percentage of the lidocaine in the lipid drug formulation is 15%-21%, 17%-21% or 17%-20%, the phospholipid is lecithin, and the lipid
  • the mass percentage in the pharmaceutical preparation is 65%-82% or 70%-75%, and the mass percentage of the soybean oil in the fatty pharmaceutical preparation is 6%-12% or 8%-10%.
  • the lipid drug preparation includes the following components (or consists of the following components): lidocaine, phospholipids (such as lecithin) and soybean oil, and the lidocaine is
  • the mass percentage of the lipid drug formulation is 3%-12%
  • the mass percentage of the phospholipid (for example, lecithin) in the lipid drug formulation is 40%-75%
  • the soybean oil is in the lipid drug formulation.
  • the mass percentage in the preparation is 20%-50%.
  • the lipid drug preparation includes the following components (or consists of the following components): lidocaine, phospholipids (such as lecithin) and soybean oil, and the lidocaine is
  • the mass percentage of the lipid drug formulation is 3%-15%
  • the mass percentage of the phospholipid (for example, lecithin) in the lipid drug formulation is 40%-80%
  • the soybean oil is in the lipid drug formulation.
  • the mass percentage in the preparation is 8%-50% or 8%-40%.
  • the lipid drug preparation may also contain bacteriostatic ingredients.
  • the antibacterial ingredient is preferably one or more of chlorhexidine, antibiotics and sulfa drugs, more preferably chlorhexidine.
  • the quality of the chlorhexidine in the lipid drug preparation is preferably 0.1% to 5%, more preferably 0.2% to 2%. In this way, the risk of infection can be reduced.
  • the peak average blood concentration is not higher than 5000 ng/mL, more preferably not higher than 2500 ng/mL (The literature agrees that it is safe for the peak blood concentration to be less than 5000ng/ml); the effective analgesic time is not shorter than 24 hours, or even not shorter than 48 hours.
  • the current mainstream postoperative analgesic method is to use an analgesic pump to infuse central nervous system analgesics into the body.
  • the typical use time of an analgesic pump is 48 hours after the operation. Therefore, it can provide The lipid drug formulation with an effective analgesic time of 48 hours can replace an analgesic pump to a large extent.
  • the present invention also provides a lipid drug preparation, the lipid drug preparation comprising lidocaine and an auxiliary material, the mass percentage of the lidocaine in the lipid drug preparation is 3%-50%, and the auxiliary material is Lipid substances that are safely absorbed by the human body or contain lipid substances that can be safely absorbed by the human body; the sum of the mass percentages of the components in the lipid drug preparation is 100%.
  • the lipid substance is preferably one or more of animal fat, vegetable fat and other fatty substances.
  • the animal fat is preferably lecithin and/or cholesterol.
  • the vegetable fat is preferably soybean lecithin, sunflower seed lecithin or vegetable oil; the vegetable oil is preferably a vegetable oil with a melting point below 35°C, more preferably a vegetable oil with a melting point below 20°C; the vegetable oil is more preferably The best place is soybean oil.
  • the lipid substance is preferably a combination of phospholipids and vegetable oil, and the lipid substance is more preferably a combination of lecithin and vegetable oil or a combination of lecithin and soybean oil.
  • the lipid drug formulation preferably includes the following components (or consists of the following components): lidocaine, phospholipids (for example, lecithin) and soybean oil, the lidocaine in the
  • the mass percentage in the lipid drug preparation is 3%-25%
  • the mass percentage of the phospholipid (for example, lecithin) in the lipid drug preparation is 50%-85% or 50%-77%.
  • the mass percentage in the lipid drug preparation is 6%-50%, 6%-45%, 7%-25% or 4%-25%.
  • the mass percentage of the lidocaine in the lipid drug formulation is 15%-21% or 17%-20%
  • the phospholipid is lecithin
  • the mass percentage in the lipid drug formulation It is 65%-82% or 70%-75%
  • the mass percentage of the soybean oil in the lipid drug preparation is 6%-12% or 8%-10%.
  • the lipid drug preparation is more suitable for being embedded in the surgical incision.
  • the lipid drug formulation preferably includes the following components (or consists of the following components): lidocaine, phospholipids (for example, lecithin) and soybean oil, the lidocaine in the
  • the mass percentage in the lipid drug preparation is 3%-12%
  • the mass percentage of the phospholipid (for example, lecithin) in the lipid drug preparation is 40%-75%
  • the soybean oil is in the lipid drug preparation The mass percentage in is 20%-50%.
  • the lipid drug formulation preferably includes the following components (or consists of the following components): lidocaine, phospholipids (for example, lecithin) and soybean oil, the lidocaine in the
  • the mass percentage of the lipid drug formulation is 3%-15%
  • the mass percentage of the phospholipid (for example, lecithin) in the lipid drug formulation is 40%-80%
  • the soybean oil is in the lipid drug formulation.
  • the mass percentage in is 8%-50% or 8%-40%.
  • the lipid drug preparation may also contain bacteriostatic ingredients.
  • the antibacterial ingredient is preferably one or more of chlorhexidine, antibiotics and sulfa drugs, more preferably chlorhexidine.
  • the quality of the chlorhexidine in the lipid drug preparation is preferably 0.1% to 5%, more preferably 0.2% to 2%.
  • the present invention also provides a lipid drug preparation, which includes lidocaine, phospholipids (for example, lecithin), vegetable oil and chlorhexidine; the mass percentage of lidocaine in the lipid drug preparation is 2%-25%, the mass percentage of the phospholipid (for example, lecithin) in the lipid drug preparation is 40%-82% or 40%-80%, and the mass of the vegetable oil in the lipid drug preparation The percentage is 15%-40%, the mass ratio of the chlorhexidine in the lipid drug preparation is 0.1%-5%; the vegetable oil is preferably soybean oil; the chlorhexidine is in the lipid drug The mass in the preparation is preferably 0.2%-2%; the sum of the mass percentages of the components in the lipid drug preparation is 100%.
  • the mass percentage of the lidocaine in the lipid drug preparation is 2%-21% or 2%-20%, the phospholipid is lecithin, and the content of the lidocaine in the lipid drug preparation
  • the mass percentage is 40%-82% or 50-70%, the mass percentage of the vegetable oil in the lipid drug preparation is 6%-40%, 15%-50%, or 15%-40%.
  • the mass ratio set in the lipid drug preparation is 0.2%-2%; the sum of the mass percentages of the components in the lipid drug preparation is 100%.
  • the fatty drug preparation is more suitable to be applied to the painful area of burns, the painful areas of burn scab removal, or the painful areas of incisions and wounds after anorectal surgery.
  • the present invention also provides an application of a lipid drug preparation in the preparation of a medicine for treating open human body surface pain or open human tissue surface pain, and the lipid drug preparation is the aforementioned lipid drug preparation.
  • the open body surface pain or open body tissue surface pain can be, for example, burn pain, pain during burn removal, incision and wound pain after anorectal surgery, or non-anorectal surgery (such as chest and abdomen surgery and Orthopedic surgery) postoperative incision pain.
  • the lipid drug preparation is applied to the open body surface pain or open body tissue surface pain at a dose less than or equal to 0.5 g of the lipid drug preparation/kg body weight to make the blood drug concentration peak If it is less than 5000ng/mL, it can even make the peak average blood concentration not higher than 2500ng/mL (for example, it may not be higher than 2000ng/mL). Under the condition that the plasma concentration of lidocaine does not exceed the above peak value, the dosage can exceed 0.5 g/kg body weight.
  • the application is applied to the open body
  • Surface pain or open human tissue surface pain refers to applying the lipid drug formulation to the open human body surface pain or open human tissue surface pain.
  • the application is applied to the open body surface pain or open body tissue surface pain
  • the term refers to embedding the lipid drug preparation into the postoperative incision.
  • the present invention also provides a treatment method using the aforementioned lipid drug preparation, which is used for treating open human tissue surface pain.
  • the open body tissue surface pain can be, for example, burn pain, pain during burn removal, incision and wound pain after anorectal surgery, or non-anorectal surgery (such as chest and abdomen surgery and orthopedic surgery).
  • the incision is painful after the operation.
  • applying the lipid drug preparation at a dose of less than or equal to 0.5 g of the lipid drug preparation/kg body weight to the painful area on the surface of the open human tissue can make the peak blood drug concentration less than 5000 ng/mL, It can even make the peak average blood drug concentration not higher than 2500ng/mL (for example, it may not be higher than 2000ng/mL). Under the condition that the plasma concentration of lidocaine does not exceed the above peak value, the dosage can exceed 0.5 g/kg body weight.
  • the method applied to the open human tissue surface pain refers to applying the lipid drug preparation to the painful area on the surface of the open human tissue.
  • the method applied to the open human tissue surface pain refers to embedding the lipid drug formulation Into the incision after the operation.
  • the present invention also provides an analgesic method using a lipid drug preparation, which is the aforementioned lipid drug preparation.
  • the analgesic method includes the following steps: apply and maintain the lipid drug formulation on an open human body surface;
  • the lipid drug preparation can be maintained on the surface of open human tissue.
  • the open body surface pain or open body tissue surface pain can be, for example, burn pain, pain during burn removal, incision and wound pain after anorectal surgery, or postoperative non-anorectal surgery
  • the incision is painful.
  • the analgesic method when the pain to be treated is postoperative incision pain after non-anorectal surgery, the analgesic method preferably includes the following steps: applying the lipid drug preparation to an unsutured or partially unsutured operation In the incision.
  • the treatment method when the pain to be treated is postoperative incision pain after non-anorectal surgery, the treatment method preferably includes the following steps: injecting or putting the lipid drug formulation into or into the surgical incision or the tissue near the surgical incision. After the lipid drug preparation is applied to the above-mentioned surgical incision or the tissue near the surgical incision, it will be slowly eroded by the contacted body fluid, thereby slowly releasing the local anesthetic contained therein. Since the erosion and release process is a slow process, the local anesthetic contained in the lipid drug preparation will not cause excessive blood concentration and can also provide long-term analgesic effects.
  • the analgesic method when the pain to be treated is burn pain, pain during burns and scab removal, or pain of incisions and wounds after anorectal surgery, the analgesic method preferably includes the following steps: Apply and maintain on the open body surface or open body tissue surface. After contacting the open human body surface or the open human tissue surface, the lipid drug preparation will be contacted by the open human body surface or the open human tissue surface, and the local anesthetics contained in it will diffuse due to the concentration gradient. Into the open body surface or open body tissue surface. Since the diffusion process is a slow process, the local anesthetic contained in the lipid drug preparation will not cause excessive blood concentration and can also provide long-term analgesic effects.
  • the components in the lipid drug preparation are uniformly mixed.
  • the lipid drug preparation of the present invention is mainly applied to open human body surfaces or open human tissue surfaces that need analgesia, and can take effect in a short time, and can obtain 12, 24, 36, 48, 72 hours, or even longer Continuous analgesic effect over time.
  • the lipid drug preparation of the present invention is applied to open body surface or open body tissue surface pain, it can provide safe, long-term and effective analgesia.
  • the lipid drug preparation of the present invention also has the advantages of room temperature storage and convenient use.
  • the lipid drug preparation of the present invention can replace the traditional central nervous system anesthetics, thereby avoiding the serious problems caused by central nervous system anesthetics. side effect.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • fatty pharmaceutical preparation M Put sodium dihydrogen phosphate, disodium hydrogen phosphate, glycerin, lidocaine, and lecithin into a container. Add water equal to the weight of lecithin. Stir to get a paste. The paste was baked in an oven at 80°C for 24 hours to evaporate the water contained in it to obtain a creamy fatty pharmaceutical preparation, which was recorded as fatty pharmaceutical preparation M.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • the carboxylated chitosan was first dissolved in 10 times its weight in water. Add glycerin, lidocaine, and lecithin. Stir to get a paste. Bake the paste in an oven at 80°C for 24 hours to evaporate the water contained in it to obtain a solid fatty pharmaceutical preparation, which is recorded as fatty pharmaceutical preparation N.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • fatty pharmaceutical preparation P Dissolve the sodium sulfate in 20 times its weight in water. Add glycerin, lidocaine, and lecithin. Stir to get a paste. The paste was baked in an oven at 80°C for 24 hours to evaporate the water contained in it to obtain a solid fatty pharmaceutical preparation, which was recorded as fatty pharmaceutical preparation P.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • lipid drug preparation Q Lipid drug formulation Q is soft and solid at 45 degrees Celsius.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • lipid drug preparation R Put lidocaine, soybean oil, lecithin, and glycerin into a container. Heat to 125°C and stir. Cool to room temperature. A cream-like lipid drug preparation is obtained, which is recorded as lipid drug preparation R.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • fatty pharmaceutical preparation S Put sodium dihydrogen phosphate, disodium hydrogen phosphate, glycerin, lidocaine, and lecithin into a container. Add water equal to the weight of lecithin. Stir to get a paste. The paste was baked in an oven at 80°C for 24 hours to evaporate the water contained in it to obtain a cream-like fatty pharmaceutical preparation, which was recorded as fatty pharmaceutical preparation S.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • lipid drug preparation T The melting temperature of the lipid drug formulation T is in the range of 25-36°C.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • lipid drug preparation U Put lidocaine, soybean oil, lecithin, and chlorhexidine in a container. Heat to 125°C and stir. Cool to room temperature. A cream-like lipid drug preparation is obtained, which is recorded as lipid drug preparation U.
  • the melting temperature of the lipid drug formulation U is in the range of 25-36°C, and it has a bacteriostatic effect. Compared with the lipid drug preparation Q, the lipid drug preparation U has a lower melting temperature and a softer texture, so it is easier to apply to open human surfaces, such as large burned surfaces.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • lipid drug preparation V Put lidocaine, soybean oil, lecithin, and chlorhexidine in a container. Heat to 125°C and stir. Cool to room temperature. A viscous oily lipid drug preparation is obtained, which is recorded as lipid drug preparation V.
  • the melting temperature of lipid drug formulation V is in the range of 15-33°C, and it has analgesic and antibacterial effects at the same time. Compared with lipid drug preparation Q, and even compared with lipid drug preparation U, lipid drug preparation V has a lower melting temperature and a softer texture, so it is easier to apply on open human surfaces, such as large burned surfaces.
  • a lipid drug preparation Its components are:
  • the preparation method of the lipid drug preparation is as follows:
  • the lipid drug preparations of Examples 1-30 all have the following properties: in the above lipid drug preparations, the excipients (other components except for local anesthetics and/or chlorhexidine) are excipients that can be safely absorbed by the human body; the above lipid drugs After the preparation is embedded in human tissues or applied on an open human body surface, under the erosion of body fluids, the lidocaine in it can be released from the above-mentioned lipid drug preparation in a slow-release manner to the above-mentioned lipid drug preparation in contact with the The surface of human tissue, and can make the patient's average blood concentration peak at maximum dose not higher than 5000ng/mL, more preferably not higher than 2500ng/mL; effective analgesia time is not shorter than 24 hours; wherein, the The maximum dose is 0.5 g of the above lipid drug preparation/kg body weight.
  • the surgeon At the end of a patient’s abdominal surgery, the surgeon first sutured the fascia and muscle layer, and then squeezed the lipid drug preparation M stored in a syringe into the surgical incision (10 cm incision length, the extruded lipid drug The strip of preparation M is also 10 cm long, and a 10 cm long lipid drug preparation M weighing 4 grams is placed along the length of the incision, and then the skin is sutured.
  • the lidocaine in the lipid drug formulation M put into the surgical incision is slowly released into the incision tissue, thereby anesthetizing the incision tissue for a long time.
  • the patient hardly felt pain for 72 hours after the operation.
  • the experience of this patient showed that the lipid drug formulation M, used according to the above-mentioned method of use, can provide effective analgesia for at least 72 hours.
  • the surgeon At the end of a patient’s abdominal surgery, the surgeon first sutured the fascia and muscle layer, and then squeezed the lipid drug preparation Q stored in a syringe into the surgical incision (10 cm incision length, uniform along the incision length Put 3 grams of lipid drug preparation Q), and then suture the skin.
  • the lidocaine in the lipid drug formulation Q put into the surgical incision is slowly released into the incision tissue.
  • the patient hardly felt pain for 72 hours after the operation.
  • the experience of this patient showed that the lipid drug formulation Q, used according to the method described, can provide effective analgesia for at least 72 hours.
  • the surgeon At the end of a patient’s abdominal surgery, the surgeon first sutures the fascia and muscle layer, and then squeezes the lipid drug formulation S stored in a syringe into the surgical incision (12 cm incision length, uniform along the incision length Put 8 grams of lipid drug preparation S), and then suture the skin.
  • the lidocaine in the lipid drug formulation S put into the surgical incision is slowly released into the incision tissue.
  • the patient hardly felt pain for 72 hours after the operation.
  • the experience of this patient showed that the lipid drug formulation S can provide effective analgesia for at least 72 hours.
  • a patient's second degree burn wound was very painful and was at risk of infection.
  • the doctor smeared the lipid drug preparation U on the wound surface, and then covered the preparation layer with gauze.
  • Lidocaine and chlorhexidine (bacteriostatic components) in the lipid drug formulation U applied on the wound surface are slowly released into the wound surface tissue, thereby achieving the purpose of long-term analgesia.
  • the patient basically felt no pain for 24 hours after the operation, and the risk of infection was greatly reduced.
  • Lidocaine and chlorhexidine (bacteriostatic components) in the lipid drug preparation U applied on the wound surface are slowly released into the wound surface tissue, thereby achieving the purpose of long-term analgesia and prevention of infection.
  • a patient's second degree burn wound was very painful and was at risk of infection.
  • the doctor smeared the lipid drug preparation V on the wound surface, and then covered the preparation layer with gauze.
  • Lidocaine and chlorhexidine (bacteriostatic components) in the lipid drug formulation V applied on the wound surface are slowly released into the wound surface tissue, thereby achieving the purpose of long-term pain relief.
  • the patient basically felt no pain for 24 hours after the operation, and the risk of infection was greatly reduced.
  • the lipid drug formulation V has a lower viscosity than the lipid drug formulation U, so it is easier to be applied to the burn wound.
  • Lipid drug preparations N, P, Q and R the lipid drug preparations of Examples 8-21 and Examples 24-30, used for surgical incisions of patients, can also provide effective analgesia for at least 72 hours.
  • the lipid drug preparation Q contains 18wt% lidocaine (3 grams contains 540 mg lidocaine in total), so the dose of lidocaine obtained by the piglet is 54 mg/kg.
  • the venous blood of the piglet was drawn and the concentration of lidocaine in the blood sample was measured by the LC-MS method.
  • the following table lists the average blood drug concentration (ng/mL) of the three piglets at these time points.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Anesthesiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种脂性药物制剂及其应用。该脂性药物制剂包括局部麻醉药和脂类物质，局部麻醉药在脂性药物制剂中的质量百分比为2％-50％，局部麻醉药为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因；脂类物质在脂性药物制剂中的质量百分比为30％-98％；所述脂性药物制剂中各组分的质量百分比之和为100％。在许多镇痛应用中，该脂性药物制剂，能够获得12、24、36、48、72小时，甚至更长时间的连续安全镇痛效果。

Description

脂性药物制剂及其应用
本申请要求申请日为2019年4月15日的中国专利申请CN201910299949.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种脂性药物制剂及其应用。
背景技术
局部麻醉药制剂被用于预防或治疗皮肤或粘膜的疼痛，例如：2％盐酸利多卡因凝胶用于减轻与晒伤有关的疼痛；恩纳(英文名称EMLA)是一种含利多卡因和丙胺卡因低点共融油滴的乳剂，其用于伴有疼痛的手术前完整皮肤的麻醉；Lidoderm是一种含5％利多卡因的固化凝胶贴剂，其用于减轻带状疱疹后遗神经痛(皮肤本身是完整的)；Pliaglis是一种含7％利多卡因和7％丁卡因低点共融油滴形的乳剂，其用于伴有疼痛的手术前完整皮肤的麻醉。但是，上述各局部麻醉药制剂均各有严重的局限性。例如：盐酸利多卡因凝胶不能麻醉完整皮肤；EMLA中的丙胺卡因会引起高铁血红蛋白血症；Pliaglis中的丁卡因会引起与酯类局部麻醉药有关的过敏反应，且丁卡因会被水解，故Pliaglis必须冷藏储存，以降低水解速度；Lidoderm无法在120分钟内，甚至4小时内麻醉完整的皮肤，且Lidoderm每次使用时间不能超过12小时。然而，上述各局部麻醉药制剂共同的局限在于不能实现长时间连续安全镇痛效果。
在许多疾病的治疗中，理想的产品是能够有6、12、18、24、30，甚至48小时或更长的连续镇痛效果。因此，寻求一种安全的，具有长期连续安全镇痛效果的药物制剂是目前亟须解决的问题。
没有皮肤或粘膜覆盖的人体组织表面，如手术切口，烧烫伤表面，创伤表面等这些开放性人体表面，常常有镇痛需求，开放性人体表面的特点是对外界物质的吸收，如局部麻醉药的吸收，没有像皮肤那样的障碍。(在本发明中，“开放性人体表面”或“开放性人体组织表面”是指没有皮肤或粘膜覆盖的人体组织表面或被不完整的皮肤或粘膜(如破损的皮肤或粘膜)覆盖的人体组织表面，包括缝合和未缝合的手术切口创面)所以，如果将一个没有缓释功能的局部麻醉药制剂放在开放性人体表面上，比如，把医院里常用的2％盐酸利多卡因施放在烧烫伤表面，该制剂所含局部麻醉药会很快被吸收进入全身血液循环，导致可能会引起严重副作用的高血药浓度和很短的镇痛效果持续时间，为此， 寻求一种能够实现缓释效果的药物制剂也是目前亟须解决的问题。
手术后切口镇痛是一个普遍要求。现今普遍使用的方法是用镇痛泵将中枢神经作用的药物，如芬太尼和杜冷丁，输入病人的体内。这些药物经过血脑屏障以后进入脑组织，与有关疼痛受体结合，从而达到镇痛的目的。但是所有这些中枢神经作用的镇痛药均可能引起严重的副作用，如呼吸抑制和成瘾性。因此，用没有中枢神经作用的局部麻醉药来控制手术后切口疼痛会是重大的进步。但是，如上所述，手术切口镇痛的局部麻醉药制剂必须以缓释的方式释放所含局部麻醉药。按照这个思路，最近Pacira Pharmaceuticals,Inc推出的产品Exparel用特殊配方的局部麻醉药布比卡因取代中枢神经镇痛药或减少中枢神经镇痛药的用量，受到了医生和病人的欢迎。但是Exparel有许多弱点:(1)制剂中包裹布比卡因的脂质体不稳定，所以Exparel必须冷藏储存和运输；(2)Exparel必须沿着手术切口进行最多达20针的复杂注射操作，使用很不方便，很费时间；(3)手术后镇痛的需求一般是至少2-3天，但是Exparel的有效镇痛效果只有24小时。因此，寻求一种能够实现长时间手术后切口镇痛的、可以方便使用的、可以在室温下运输和储存的药物制剂同样是目前亟须解决的问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中的局部麻醉药制剂不能实现长时间连续安全镇痛效果的缺陷，而提供一种新型的脂性药物制剂及其应用。
本发明的脂性药物制剂，主要应用于需要镇痛的开放性人体表面，能够在很短时间内起效，能够获得12、24、36、48、72小时，甚至更长时间的连续镇痛效果。将本发明的脂性药物制剂，用于开放性人体表面疼痛时，能够提供安全、长期和有效的镇痛。
本发明中，所述镇痛效果是指与不含镇痛药物成分的安慰剂相比有统计意义的镇痛效果。与安慰剂相比的镇痛效果可以用国际通用的Visual Analog Scale等疼痛测试方法测得。
本发明的脂性药物制剂还具有室温储存和使用方便等优点，在镇痛应用中，本发明的脂性药物制剂可以代替传统使用的中枢神经麻醉药，从而避免了中枢神经麻醉药会带来的严重副作用。
本发明解决上述技术问题所采用的技术方案之一如下：
本发明提供一种脂性药物制剂，所述脂性药物制剂包括局部麻醉药和脂类物质，所述局部麻醉药在所述脂性药物制剂中的质量百分比为2％-50％，所述局部麻醉药为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲 哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因；所述脂类物质在所述脂性药物制剂中的质量百分比为30％-98％；所述脂性药物制剂中各组分的质量百分比之和为100％。
上述脂性药物制剂中，所述局部麻醉药在所述脂性药物制剂中的质量百分比较佳地为3％-50％、10％-50％、20％-50％、6％-50％、6％-40％、7％-35％、8％-30％、8％-24％、10％-24％或3％-8％，例如可为约18％、约25％、18％或25％。
上述脂性药物制剂中，所述局部麻醉药较佳地为利多卡因、布比卡因或丁卡因，更佳地为利多卡因。
上述脂性药物制剂中，所述脂类物质在所述脂性药物制剂中的质量百分比较佳地为50％-98％，更佳地为55％-84％。
上述脂性药物制剂中，所述脂性药物制剂的熔化温度较佳地在37℃以上，更佳地在45℃以上，进一步更佳地为45-200℃，再进一步更佳地为45-80℃。上述熔化温度范围内的脂性药物制剂，在施放进人体组织后，不会变成可以自由流动的液体，从而更好地实现缓释的效果。
上述脂性药物制剂中，所述脂性药物制剂的熔化温度也可以为25-36℃，也可以为15-33℃。上述熔化温度范围内的脂性药物制剂，在涂抹在人体组织表面后，可以变成粘滞但是可以流动的液体，从而更容易到达需要被镇痛的人体组织表面。这在某些镇痛应用中非常重要。例如，肛肠手术后的肛门和/或接近肛门的结肠的创口经常非常疼痛。将熔化温度为25-36℃或15-33℃的所述脂性药物制剂涂抹在肛门外或内后，所述脂性药物制剂的流动性可以使其接触到肛门内外的所有需要被镇痛的表面或切口。
上述脂性药物制剂中，所述脂性药物制剂还可含有抑菌成分；所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定。所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％，更佳地为0.2％-2％。
上述脂性药物制剂中，所述脂性药物制剂还可含有水溶性物质。所述水溶性物质例如可为甘油。所述水溶性物质在所述脂性药物制剂中的质量百分比较佳地为8％-12％。
上述脂性药物制剂中，所述脂性药物制剂还可含有甲壳素和/或甲壳素的衍生物。所述甲壳素的衍生物较佳地为羧化壳聚糖。所述羧化壳聚糖在所述脂性药物制剂中的质量百分比较佳地为3％-5％。含有甲壳素和/或甲壳素的衍生物的上述脂性药物制剂，具有更高的硬度和一定的抑菌能力。
上述脂性药物制剂中，所述脂性药物制剂还可含有质酸或质酸钠。所述质酸或质酸钠在所述脂性药物制剂中的质量百分比较佳地为4％-8％。所述质酸可以是未交联的质酸 或交联的质酸。所述质酸钠可以是未交联的质酸钠或交联的质酸钠。含有质酸或质酸钠的上述脂性药物制剂，可以在接触并吸收体液后形成凝胶。
上述脂性药物制剂中，所述脂性药物制剂还可含有pH缓冲对。所述pH缓冲对在所述脂性药物制剂中的质量百分比较佳地为4-18％，例如为12％。所述pH缓冲对较佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对、磷酸氢二钾和磷酸二氢钾组成的pH缓冲对、四硼酸钠和氢氧化钠组成的pH缓冲对或三羟甲基氨基甲烷和HCl组成的pH缓冲对，更佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对或四硼酸钠和氢氧化钠组成的pH缓冲对，进一步更佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对。
上述脂性药物制剂中，所述脂类物质可为本领域常规使用的脂类物质，通常指的是动物脂肪、植物脂肪和其他脂肪类物质中的一种或多种，所述其他脂肪类物质指的是中国，美国，或其他国家食药监局批准的除动物脂肪和植物脂肪之外的药用或食用脂肪类物质。
所述动物脂肪较佳地为卵磷脂和/或胆固醇。所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油。所述植物油更佳地为大豆油。
上述脂性药物制剂中，较佳地，所述脂类物质为磷脂和植物油的组合，更佳地为卵磷脂和植物油的组合或者卵磷脂和大豆油的组合。更佳地，所述磷脂在所述脂性药物制剂中的质量百分比为40％-80％，且所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％。
本发明中，所述磷脂是指从任何原料中提取的磷脂，包括卵磷脂，大豆磷脂，葵花籽磷脂，和其他来源的磷脂。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下质量百分比的各组分(或由如下质量百分比的各组分组成)：3％-50％的利多卡因、30％-90％的磷脂(例如为卵磷脂)和3％-20％的植物油。所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油。所述植物油更佳地为大豆油。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下质量百分比的各组分(或由如下质量百分比的各组分组成)：5％-50％的利多卡因、40％-85％的磷脂(例如为卵磷脂)和3％-20％的植物油。所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油。所述植物油更佳地为大豆油。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下质量百分比的各组分(或由如下质量百分比的各组分组成)：15％-25％的利多卡因、65％-85％的磷脂和6％-15％的 植物油。所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油。所述植物油更佳地为大豆油。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下质量百分比的各组分(或由如下质量百分比的各组分组成)：3％-8％的利多卡因、40％-70％的磷脂(例如为卵磷脂)和25％-55％的植物油。所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油。所述植物油更佳地为大豆油。
上述脂性药物制剂中，所述脂性药物制剂还可含有质量百分比为8％-12％的甘油。
上述脂性药物制剂中，所述脂性药物制剂还可含有质量百分比为3％-5％(例如可为4％)的羧化壳聚糖。
上述脂性药物制剂中，所述脂性药物制剂还可含有质量百分比为4％-8％的质酸钠。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下质量百分比的各组分(或由如下质量百分比的各组分组成)：5％-30％(例如可为20％)的利多卡因、55％-85％(例如可为72％)的磷脂(例如为卵磷脂)和8％-15％(例如可为8％)的质酸钠。
本发明解决上述技术问题所采用的技术方案之二如下：
本发明还提供一种脂性药物制剂，所述脂性药物制剂包括利多卡因和辅料，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-50％，较佳地为14％-50％，更佳地为15％-50％，所述辅料为能够被人体安全吸收的辅料，且所述辅料还含有脂类物质，所述脂类物质在所述脂性药物制剂中的质量百分比为30％以上，且不为100％；所述脂性药物制剂中各组分的质量百分比之和为100％；
所述脂性药物制剂埋入人体组织后，在体液的侵蚀下，所述脂性药物制剂中的利多卡因能够以缓释的方式从所述脂性药物制剂中被释放到所述脂性药物制剂所接触的所述人体组织的表面，且能够使得病人在最大剂量时的平均血药浓度峰值不高于5000ng/mL，较佳地不高于2500ng/mL，(例如也可不高于2000ng/mL)，有效镇痛时间不短于24小时；其中，所述最大剂量为0.5克所述脂性药物制剂/公斤体重。
本发明的发明人在研究过程中发现，基于医学和配方稳定性的需要，满足上述理想条件的配方即可实现长时间连续安全镇痛效果。
上述脂性药物制剂中，所述辅料较佳地均为已经被中国，美国，或其他国家食药监局批准销售的药物制剂中的辅料。
上述脂性药物制剂中，较佳地，所述有效镇痛时间不短于48小时。
上述脂性药物制剂中，较佳地，所述脂类物质为动物脂肪、植物脂肪和其他脂肪类物质中的一种或多种，所述其他脂肪类物质指的是中国，美国，或其他国家食药监局批 准的除动物脂肪和植物脂肪之外的药用或食用的脂肪类物质。
其中，所述动物脂肪较佳地为卵磷脂和/或胆固醇。
其中，所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油；所述植物油更佳地为大豆油。
其中，所述脂类物质较佳地为磷脂和植物油的组合，更佳地为卵磷脂和植物油的组合或者卵磷脂和大豆油的组合。
上述脂性药物制剂中，较佳地，所述脂性药物制剂在高温灭菌条件下不分层，所述高温灭菌条件的温度为121℃以上，例如可为121℃，所述高温灭菌条件的时间为15分钟以上；例如可为15分钟。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、7％-25％或4％-25％。更佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为15％-21％、17％-21％或17％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为65％-82％或者70％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-12％或者8％-10％。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％。
上述脂性药物制剂中，较佳地，所述脂性药物制剂包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8％-40％。
上述脂性药物制剂中，所述脂性药物制剂还可含有抑菌成分。所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定。其中，所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％，更佳地为0.2％-2％。如此，可降低感染的风险。
上述脂性药物制剂，在埋入人体组织后，由于利多卡因的浓度梯度的驱使及人体体 液的侵蚀下，利多卡因以缓释的方式从所述脂性药物制剂中被释放到所述脂性药物制剂所接触的所述人体组织的表面；在最大剂量(0.5克所述脂性药物制剂/公斤体重)时，平均血药浓度峰值不高于5000ng/mL，更佳地不高于2500ng/mL(文献一致认为血药浓度峰值小于5000ng/ml是安全的)；有效镇痛时间不短于24小时，甚至不短于48小时。此处，还需要说明的是，现在的主流手术后镇痛方法是用镇痛泵将中枢神经作用的镇痛药输入体内，典型的镇痛泵使用时间是手术后48小时，因此，可以提供48小时有效镇痛时间的所述脂性药物制剂可以在很大程度上取代镇痛泵。
本发明解决上述技术问题所采用的技术方案之三如下：
本发明还提供一种脂性药物制剂，所述脂性药物制剂包括利多卡因和辅料，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-50％，所述辅料为能够被人体安全吸收的脂类物质或者含能够被人体安全吸收的脂类物质；所述脂性药物制剂中各组分的质量百分比之和为100％。
上述脂性药物制剂中，所述脂类物质较佳地为动物脂肪、植物脂肪和其他脂肪类物质中的一种或多种。
其中，所述动物脂肪较佳地为卵磷脂和/或胆固醇。
其中，所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油；所述植物油更佳地为大豆油。
其中，所述脂类物质较佳地为磷脂和植物油的组合，所述脂类物质更佳地为卵磷脂和植物油的组合或者卵磷脂和大豆油的组合。
上述脂性药物制剂中，所述脂性药物制剂较佳地包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、7％-25％或4％-25％。更佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为15％-21％或者17％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为65％-82％或者70％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-12％或者8％-10％。该脂性药物制剂更适合埋入手术切口内。
上述脂性药物制剂中，所述脂性药物制剂较佳地包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为 40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％。
上述脂性药物制剂中，所述脂性药物制剂较佳地包括如下组分(或由如下组分组成)：利多卡因、磷脂(例如为卵磷脂)和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8％-40％。
上述脂性药物制剂中，所述脂性药物制剂还可含有抑菌成分。所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定。其中，所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％，更佳地为0.2％-2％。
本发明解决上述技术问题所采用的技术方案之四如下：
本发明还提供一种脂性药物制剂，所述脂性药物制剂包括利多卡因、磷脂(例如为卵磷脂)、植物油和氯己定；所述利多卡因在所述脂性药物制剂中的质量百分比为2％-25％，所述磷脂(例如为卵磷脂)在所述脂性药物制剂中的质量百分比为40％-82％或者40％-80％，所述植物油在所述脂性药物制剂中的质量百分比为15％-40％，所述氯己定在所述脂性药物制剂中的质量比为0.1％-5％；所述植物油较佳地为大豆油；所述氯己定在所述脂性药物制剂中的质量比较佳地为0.2％-2％；所述脂性药物制剂中各组分的质量百分比之和为100％。
其中，较佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为2％-21％或者2％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为40％-82％或者50-70％，所述植物油在所述脂性药物制剂中的质量百分比为6％-40％、15％-50％或15％-40％，所述氯己定在所述脂性药物制剂中的质量比为0.2％-2％；所述脂性药物制剂中各组分的质量百分比之和为100％。该脂性药物制剂更适合涂抹于烧伤疼痛处、烧伤去痂时的疼痛处或肛肠手术后的切口和创面的疼痛处。
本发明解决上述技术问题所采用的技术方案之五如下：
本发明还提供一种脂性药物制剂在制备治疗开放性人体表面疼痛或者开放性人体组织表面疼痛的药物中的应用，所述脂性药物制剂为前述的脂性药物制剂。
上述应用中，所述开放性人体表面疼痛或者开放性人体组织表面疼痛例如可为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术(如胸腹部手术和骨科手术)后的手术后切口疼痛。
上述应用中，将所述脂性药物制剂以小于或等于0.5克所述脂性药物制剂/公斤体重的剂量应用于所述开放性人体表面疼痛或者开放性人体组织表面疼痛处后能够使得血药浓度峰值小于5000ng/mL，甚至能够使得平均血药浓度峰值不高于2500ng/mL(例如也可 不高于2000ng/mL)。在利多卡因血药浓度不超过上述峰值的条件下，使用剂量可以超过0.5克/公斤体重。
当所述开放性人体表面疼痛或者开放性人体组织表面疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛时，较佳地，所述应用于所述开放性人体表面疼痛处或者开放性人体组织表面疼痛处指的是将所述脂性药物制剂涂抹在所述开放性人体表面疼痛处或者开放性人体组织表面疼痛处。
当所述开放性人体表面疼痛或者开放性人体组织表面疼痛为非肛肠手术后的手术后切口疼痛时，较佳地，所述应用于所述开放性人体表面疼痛处或者开放性人体组织表面疼痛处指的是将所述脂性药物制剂埋入所述手术后切口。
本发明解决上述技术问题所采用的技术方案之六如下：
本发明还提供一种采用如前所述的脂性药物制剂的治疗方法，所述治疗方法用于治疗开放性人体组织表面疼痛。
上述治疗方法中，所述开放性人体组织表面疼痛例如可为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术(如胸腹部手术和骨科手术)后的手术后切口疼痛。
上述治疗方法中，将所述脂性药物制剂以小于或等于0.5克所述脂性药物制剂/公斤体重的剂量应用于所述开放性人体组织表面疼痛处后能够使得血药浓度峰值小于5000ng/mL，甚至能够使得平均血药浓度峰值不高于2500ng/mL(例如也可不高于2000ng/mL)。在利多卡因血药浓度不超过上述峰值的条件下，使用剂量可以超过0.5克/公斤体重。
当所述开放性人体组织表面疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛时，较佳地，所述应用于所述开放性人体组织表面疼痛处的方法指的是将所述脂性药物制剂涂抹在所述开放性人体组织表面疼痛处。
当所述开放性人体组织表面疼痛为非肛肠手术后的手术后切口疼痛时，较佳地，所述应用于所述开放性人体组织表面疼痛处的方法指的是将所述脂性药物制剂埋入所述手术后切口。
本发明解决上述技术问题所采用的技术方案之七如下：
本发明还提供一种采用脂性药物制剂的镇痛方法，所述脂性药物制剂为前述的脂性药物制剂。所述镇痛方法包括如下步骤：将所述脂性药物制剂施用并维持在开放性人体表面即可；
或者，将所述脂性药物制剂维持在开放性人体组织表面即可。
上述镇痛方法中，所述开放性人体表面疼痛或者开放性人体组织表面疼痛例如可为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术后的手术后切口疼痛。
上述镇痛方法中，当治疗的疼痛为非肛肠手术后的手术后切口疼痛时，所述镇痛方法较佳地包括如下步骤：将所述脂性药物制剂施放在未缝合或部分未缝合的手术切口中。或者，当治疗的疼痛为非肛肠手术后的手术后切口疼痛时，所述治疗方法较佳地包括如下步骤：将所述脂性药物制剂注射进入或放入手术切口或手术切口附近的组织中。所述脂性药物制剂被施放在上述手术切口中或手术切口附近的组织里后，会被所接触的体液慢慢地侵蚀，从而慢慢地释放出其所含的局部麻醉药。由于所述的侵蚀和释放过程是一个缓慢的过程，所述脂性药物制剂所含的局部麻醉药不会引起过高的血药浓度，也可以提供长时间的镇痛效果。
上述镇痛方法中，当治疗的疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛时，所述镇痛方法较佳地包括如下步骤：将所述脂性药物制剂涂抹并维持在所述开放性人体表面或开放性人体组织表面上。接触所述开放性人体表面或开放性人体组织表面后，所述脂性药物制剂会被所述开放性人体表面或开放性人体组织表面接触，其所含的局部麻醉药会因为浓度梯度驱使而扩散进入所述开放性人体表面或开放性人体组织表面。由于所述扩散过程是一个缓慢的过程，所述脂性药物制剂所含的局部麻醉药不会引起过高的血药浓度，也可以提供长时间的镇痛效果。
本发明中，所述脂性药物制剂中的各组分混合均匀。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明的积极进步效果在于：
本发明的脂性药物制剂，主要应用于需要镇痛的开放性人体表面或开放性人体组织表面，能够在很短时间内起效，能够获得12、24、36、48、72小时，甚至更长时间的连续镇痛效果。将本发明的脂性药物制剂用于开放性人体表面或开放性人体组织表面疼痛时，能够提供安全、长期和有效的镇痛。
本发明的脂性药物制剂还具有室温储存和使用方便等优点，在镇痛应用中，本发明的脂性药物制剂可以代替传统使用的中枢神经麻醉药，从而避免了中枢神经麻醉药会带来的严重副作用。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 55％
磷酸二氢钠 0.07％
磷酸氢二钠 11.93％
利多卡因 24％
甘油 9％
所述脂性药物制剂的制备方法如下：
将磷酸二氢钠、磷酸氢二钠、甘油、利多卡因、卵磷脂放入一个容器中。加入与卵磷脂等重的量的水。搅拌，得到一种糊状物。将此糊状物在80℃的烤箱里烤24小时，以蒸发完所含的水，即得一种膏状的脂性药物制剂，记为脂性药物制剂M。
实施例2
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 58％
羧化壳聚糖 4％
利多卡因 26％
甘油 12％
所述脂性药物制剂的制备方法如下：
将羧化壳聚糖先溶解在其10倍重量的水中。加入甘油、利多卡因、卵磷脂。搅拌，得到一种糊状物。将此糊状物在80℃的烤箱里烤24小时，以蒸发完所含的水，即得一种固体的脂性药物制剂，记为脂性药物制剂N。
实施例3
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 58％
质酸钠 4％
利多卡因 26％
甘油 12％
所述脂性药物制剂的制备方法如下：
将质酸钠先溶解在其20倍重量的水中。加入甘油、利多卡因、卵磷脂。搅拌，得到一种糊状物。将此糊状物在80℃的烤箱里烤24小时，以蒸发完所含的水，即得一种固体的脂性药物制剂，记为脂性药物制剂P。
实施例4
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 73％
利多卡因 18％
大豆油 9％
所述脂性药物制剂的制备方法如下：
将利多卡因、大豆油和卵磷脂放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种膏状的脂性药物制剂，记为脂性药物制剂Q。脂性药物制剂Q在45摄氏度时是柔软的固体。
实施例5
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 59％
利多卡因 25％
大豆油 8％
甘油 8％
所述脂性药物制剂的制备方法如下：
将利多卡因、大豆油，卵磷脂、甘油放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种膏状的脂性药物制剂，记为脂性药物制剂R。
实施例6
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 74％
磷酸二氢钠 0.07％
磷酸氢二钠 11.93％
利多卡因 5％
甘油 9％
所述脂性药物制剂的制备方法如下：
将磷酸二氢钠、磷酸氢二钠、甘油、利多卡因、卵磷脂放入一个容器中。加入与卵磷脂等重的量的水。搅拌，得到一种糊状物。将此糊状物在80℃的烤箱里烤24小时，以蒸发完所含的水，即得一种膏状的脂性药物制剂，记为脂性药物制剂S。
实施例7
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 66％
利多卡因 17％
大豆油 17％
所述脂性药物制剂的制备方法如下：
将利多卡因、大豆油，卵磷脂放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种膏状的脂性药物制剂，记为脂性药物制剂T。脂性药物制剂T的熔化温度在25-36℃的范围内。
实施例8-14
将实施例1-7中的利多卡因置换为布比卡因。
实施例15-21
将实施例1-7中的利多卡因置换为丁卡因。
实施例22
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 63.5％
利多卡因 15％
大豆油 20％
氯己定(抑菌成分) 1.5％
所述脂性药物制剂的制备方法如下：
将利多卡因、大豆油、卵磷脂和氯己定放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种膏状的脂性药物制剂，记为脂性药物制剂U。脂性药物制剂U的熔化 温度在25-36℃的范围内，且有抑菌作用。跟脂性药物制剂Q相比，脂性药物制剂U熔化温度更低，质地更软，所以更容易涂抹在开放性的人体表面上，比如大面积的烧伤表面。
实施例23
一种脂性药物制剂。其组分为：
成分 质量百分比
卵磷脂 56.5％
利多卡因 5％
大豆油 38％
氯己定(抑菌成分) 0.5％
所述脂性药物制剂的制备方法如下：
将利多卡因、大豆油、卵磷脂和氯己定放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种粘滞油状的脂性药物制剂，记为脂性药物制剂V。脂性药物制剂V的熔化温度在15-33℃范围内，并同时具有镇痛和抑菌作用。跟脂性药物制剂Q相比，甚至跟脂性药物制剂U相比，脂性药物制剂V的熔化温度更低，质地更软，所以更容易涂抹在开放性的人体表面上，比如大面积的烧伤表面。
实施例24-30
一种脂性药物制剂。其组分为：
实施例 利多卡因 卵磷脂 大豆油 氯己定 羧化壳聚糖 质酸钠 总计
24 2wt％ 90wt％ 7.9wt％ 0.1wt％ / / 100wt％
25 3wt％ 85wt％ 9wt％ 0.2wt％ / 2.8wt％ 100wt％
26 5wt％ 80wt％ 13wt％ 2wt％ / / 100wt％
27 7wt％ 75wt％ 10wt％ / 4wt％ 4wt％ 100wt％
28 15wt％ 54wt％ 30wt％ 1wt％ / / 100wt％
29 25wt％ 55wt％ 19wt％ 1wt％ / / 100wt％
30 30wt％ 50wt％ 20wt％ / / / 100wt％
所述脂性药物制剂的制备方法如下：
将各组分放入一个容器中。加热至125℃并搅拌。冷却到室温。即得一种粘滞油状的脂性药物制剂。
实施例1-30的脂性药物制剂均具备如下性质：上述脂性药物制剂中，辅料(除局部麻醉药和/或氯己定之外的其余组分)为能够被人体安全吸收的辅料；上述脂性药物制剂埋入人体组织后或施用在开放性人体表面后，在体液的侵蚀下，其中的利多卡因能够以缓释的方式从上述脂性药物制剂中被释放到上述脂性药物制剂所接触的所述人体组织的表面，且能够使得病人在最大剂量时的平均血药浓度峰值不高于5000ng/mL，更佳地不 高于2500ng/mL；有效镇痛时间不短于24小时；其中，所述最大剂量为0.5克上述脂性药物制剂/公斤体重。
效果实施例1
一个病人的腹部手术结束时，手术医生先把筋膜和肌肉层缝合，然后将存放在一个注射器中的脂性药物制剂M挤出来放入到手术切口内(10厘米切口长度，挤出的脂性药物制剂M长条也是10厘米长，沿着切口长度放入10厘米长的脂性药物制剂M重4克)，然后缝合皮层。
被放入手术切口的脂性药物制剂M中的利多卡因被缓慢地释放到切口组织中去，从而长时间地麻醉切口组织。该病人在手术后的72小时基本上没有感觉到疼痛。而同样的手术病人，如果不用任何镇痛药物，手术后的至少3天内会有剧烈的疼痛。此病人的经历显示脂性药物制剂M，按照上述使用方法使用，可以提供至少72小时的有效镇痛。
效果实施例2
一个病人的腹部手术结束时，手术医生先把筋膜和肌肉层缝合，然后将存放在一个注射器中的脂性药物制剂Q挤出来放入到手术切口内(10厘米切口长度，沿着切口长度均匀放入3克脂性药物制剂Q)，然后缝合皮层。
被放入手术切口的脂性药物制剂Q中的利多卡因被缓慢地释放到切口组织中去。该病人在手术后的72小时基本上没有感觉到疼痛。而同样的手术病人，如果不用任何镇痛药物，手术后至少3天内会有剧烈的疼痛。此病人的经历显示脂性药物制剂Q，按照所述方法使用，可以提供至少72小时的有效镇痛。
效果实施例3
一个病人的腹部手术结束时，手术医生先把筋膜和肌肉层缝合，然后将存放在一个注射器中的脂性药物制剂S挤出来放入到手术切口内(12厘米切口长度，沿着切口长度均匀放入8克脂性药物制剂S)，然后缝合皮层。
被放入手术切口的脂性药物制剂S中的利多卡因被缓慢地释放到切口组织中去。该病人在手术后的72小时基本上没有感觉到疼痛。而同样的手术病人，如果不用任何镇痛药物，手术后至少3天内会有剧烈的疼痛。此病人的经历显示脂性药物制剂S可以提供至少72小时的有效镇痛。
效果实施例4
一个病人的二度烧伤创面非常疼痛，并且有感染的风险。医生把脂性药物制剂U涂抹在所述创面上，然后用纱布盖住制剂层。
被涂抹在所述创面上的脂性药物制剂U中的利多卡因和氯己定(抑菌成分)被缓慢 地释放到所述创面组织中去，从而达到了长期镇痛的目的。该病人在手术后的24小时基本上没有感觉到疼痛，而且感染的风险也大大降低。
效果实施例5
一个病人肛瘘手术后的创面非常疼痛，并且有感染的风险。医生把脂性药物制剂U涂抹在所述创面上。病人的疼痛，尤其是排便时的疼痛，大大减轻。
被涂抹在所述创面上的脂性药物制剂U中的利多卡因和氯己定(抑菌成分)被缓慢地释放到所述创面组织中去，从而达到了长期镇痛和防止感染的目的。
效果实施例6
一个病人的二度烧伤创面非常疼痛，并且有感染的风险。医生把脂性药物制剂V涂抹在所述创面上，然后用纱布盖住制剂层。
被涂抹在所述创面上的脂性药物制剂V中的利多卡因和氯己定(抑菌成分)被缓慢地释放到所述创面组织中去，从而达到了长期镇痛的目的。该病人在手术后的24小时基本上没有感觉到疼痛，而且感染的风险也大大降低。
脂性药物制剂V比脂性药物制剂U粘度更低，所以更容易被涂抹在所述烧伤创面。
效果实施例7
脂性药物制剂N、P、Q和R、实施例8-21及实施例24-30的脂性药物制剂，用于病人的手术切口，也可以提供至少72小时的有效镇痛。
效果实施例8
将3克本发明的脂性药物制剂Q放入到1只约10公斤重的小猪的腹部的还没有进行皮层缝合的5厘米长的手术切口(此时t＝0)中，然后，进行皮层缝合。这样，脂性药物制剂Q被封闭在已缝合的筋膜层和皮层之间。其中，脂性药物制剂Q含有18wt％利多卡因(3克共含540毫克利多卡因)，所以小猪得到的利多卡因剂量是54mg/kg。
在接下来的72小时中的事先设定的时间点上，抽取小猪的静脉血并用LC-MS方法测量血样中的利多卡因浓度。
用另外两个小猪重复上述实验。
下表列出在这些时间点上三只小猪的平均血药浓度(ng/mL)。
下表中，最右栏列出的是Ikeda等人在参考文献(Pharmacokinetics of Lidocaine,Bupivacaine,and Levobupivacaine in Plasma and Brain in Awake Rats；Yuko Ikeda等；Anesthesiology 2010；112:1396-1403)中所报告的将60mg/kg剂量的利多卡因用2小时匀速肌肉滴注的方法给药后的血药浓度随时间的变化。此外，由于Ikeda等只报告了前4个小时的数据，4小时以后的数据根据业内公认的利多卡因消除半衰期＝2小时的理论计算， 其中，消除半衰期的英文为elimination half-life。
Figure PCTCN2020084832-appb-000001
由上表中数据可知，虽然剂量相似，但是脂性药物制剂Q所引起的利多卡因血药浓度峰值远低于参考文献所采用的制剂所引起的利多卡因血药浓度峰值(业内公认当利多卡因血药浓度大于等于5000ng/mL会引起心率加快等副作用)，且前者的持续时间远长于后者。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这仅是举例说明，本发明的保护范围是由所附权利要求书限定的。本领域的技术人员在不背离本发明的原理和实质的前提下，可以对这些实施方式作出多种变更或修改，但这些变更和修改均落入本发明的保护范围。

Claims (20)

  1. 一种脂性药物制剂，其特征在于，所述脂性药物制剂包括局部麻醉药和脂类物质，所述局部麻醉药在所述脂性药物制剂中的质量百分比为2％-50％，所述局部麻醉药为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因；所述脂类物质在所述脂性药物制剂中的质量百分比为30％-98％；所述脂性药物制剂中各组分的质量百分比之和为100％。
  2. 如权利要求1所述的脂性药物制剂，其特征在于，所述局部麻醉药在所述脂性药物制剂中的质量百分比为3％-50％、10％-50％、20％-50％、6％-50％、6％-40％、7％-35％、8％-30％、8％-24％、10％-24％或3％-8％；
    和/或，所述局部麻醉药为利多卡因、布比卡因或丁卡因，较佳地为利多卡因；
    和/或，所述脂类物质在所述脂性药物制剂中的质量百分比为50％-98％，较佳地为55％-84％。
  3. 如权利要求1或2所述的脂性药物制剂，其特征在于，所述脂性药物制剂的熔化温度在37℃以上，较佳地在45℃以上，更佳地为45-200℃，进一步更佳地为45-80℃；
    或者，所述脂性药物制剂的熔化温度为25-36℃；
    或者，所述脂性药物制剂的熔化温度为15-33℃。
  4. 如权利要求1-3任一项所述的脂性药物制剂，其特征在于，所述脂性药物制剂含有抑菌成分；所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定；其中，所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％，更佳地为0.2％-2％。
  5. 如权利要求1-4任一项所述的脂性药物制剂，其特征在于，所述脂性药物制剂含有水溶性物质，所述水溶性物质较佳地为甘油，所述水溶性物质在所述脂性药物制剂中的质量百分比较佳地为8％-12％；
    和/或，所述脂性药物制剂含有甲壳素和/或甲壳素的衍生物，所述甲壳素的衍生物较佳地为羧化壳聚糖，所述羧化壳聚糖在所述脂性药物制剂中的质量百分比较佳地为3％-5％；
    和/或，所述脂性药物制剂含有质酸或质酸钠，所述质酸或质酸钠在所述脂性药物制剂中的质量百分比较佳地为4％-8％；
    和/或，所述脂性药物制剂含有pH缓冲对；所述pH缓冲对在所述脂性药物制剂中的 质量百分比较佳地为4％-18％；所述pH缓冲对较佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对、磷酸氢二钾和磷酸二氢钾组成的pH缓冲对、四硼酸钠和氢氧化钠组成的pH缓冲对或三羟甲基氨基甲烷和HCl组成的pH缓冲对，更佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对或四硼酸钠和氢氧化钠组成的pH缓冲对，进一步更佳地为磷酸氢二钠和磷酸二氢钠组成的pH缓冲对。
  6. 如权利要求1-5任一项所述的脂性药物制剂，其特征在于，所述脂类物质为动物脂肪和/或植物脂肪；所述动物脂肪较佳地为卵磷脂和/或胆固醇；所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油；所述植物油较佳地为大豆油；
    和/或，所述脂类物质为磷脂和植物油的组合；较佳地，所述脂类物质为卵磷脂和植物油的组合或者卵磷脂和大豆油的组合；其中，更佳地，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-80％，且所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％。
  7. 如权利要求1所述的脂性药物制剂，其特征在于，所述脂性药物制剂包括如下质量百分比的各组分：3％-50％的利多卡因、30％-90％的磷脂和3％-20％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：5％-50％的利多卡因、40％-85％的磷脂和3％-20％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：15％-25％的利多卡因、65％-85％的磷脂和6％-15％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：3％-8％的利多卡因、40％-70％的磷脂和25％-55％的植物油；
    其中，所述脂性药物制剂包括如下质量百分比的各组分：3％-50％的利多卡因、30％-90％的卵磷脂和3％-20％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：5％-50％的利多卡因、40％-85％的卵磷脂和3％-20％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：15％-25％的利多卡因、65％-85％的卵磷脂和6％-15％的植物油；或者，所述脂性药物制剂包括如下质量百分比的各组分：3％-8％的利多卡因、40％-70％的卵磷脂和25％-55％的植物油；
    其中，所述脂性药物制剂较佳地含有质量百分比为8％-12％的甘油；
    其中，所述脂性药物制剂较佳地含有质量百分比为3％-5％的羧化壳聚糖；
    其中，所述脂性药物制剂较佳地含有质量百分比为4％-8％的质酸钠。
  8. 如权利要求1所述的脂性药物制剂，其特征在于，所述脂性药物制剂包括如下质量百分比的各组分：5％-30％的利多卡因、55％-85％的磷脂和8％-15％的质酸钠；
    较佳地，所述脂性药物制剂包括如下质量百分比的各组分：5％-30％的利多卡因、55％- 85％的卵磷脂和8％-15％的质酸钠。
  9. 一种脂性药物制剂，其特征在于，所述脂性药物制剂包括利多卡因和辅料，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-50％，所述辅料为能够被人体安全吸收的辅料，且所述辅料还含有脂类物质，所述脂类物质在所述脂性药物制剂中的质量百分比为30％以上，且不为100％；所述脂性药物制剂中各组分的质量百分比之和为100％；
    所述脂性药物制剂埋入人体组织后，在体液的侵蚀下，所述脂性药物制剂中的利多卡因能够以缓释的方式从所述脂性药物制剂中被释放到所述脂性药物制剂所接触的所述人体组织的表面，且能够使得病人在最大剂量时的平均血药浓度峰值不高于5000ng/mL，较佳地不高于2500ng/mL，有效镇痛时间不短于24小时；其中，所述最大剂量为0.5克所述脂性药物制剂/公斤体重。
  10. 如权利要求9所述的脂性药物制剂，其特征在于，所述辅料均为已经被中国或美国国家食药监局批准销售的药物制剂中的辅料；和/或，所述有效镇痛时间不短于48小时；
    和/或，所述脂类物质为动物脂肪、植物脂肪和其他脂肪类物质中的一种或多种；
    其中，所述动物脂肪较佳地为卵磷脂和/或胆固醇；
    其中，所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油；所述植物油更佳地为大豆油；
    其中，所述脂类物质较佳地为磷脂和植物油的组合，更佳地为卵磷脂和植物油的组合或者卵磷脂和大豆油的组合。
  11. 如权利要求9或10所述的脂性药物制剂，其特征在于，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述磷脂在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、4％-25％或7％-25％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述卵磷脂在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、4％-25％或7％-25％；
    其中，较佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为15％-21％、17％-21％或17％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为62％- 82％或者70％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-12％或者8％-10％；
    或者，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述磷脂在所述脂性药物制剂中的质量百分比为40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％；
    或者，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述磷脂在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8-40％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8％-40％。
  12. 如权利要求9-11任一项所述的脂性药物制剂，其特征在于，所述脂性药物制剂含有抑菌成分；所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定；其中，所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％，更佳地为0.2％-2％。
  13. 一种脂性药物制剂，其特征在于，所述脂性药物制剂包括利多卡因和辅料，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-50％，所述辅料为能够被人体安全吸收的脂类物质或者含能够被人体安全吸收的脂类物质；所述脂性药物制剂中各组分的质量百分比之和为100％。
  14. 如权利要求13所述的脂性药物制剂，其特征在于，所述脂类物质为动物脂肪、植物脂肪和其他脂肪类物质中的一种或多种；
    其中，所述动物脂肪较佳地为卵磷脂和/或胆固醇；
    其中，所述植物脂肪较佳地为大豆磷脂、葵花籽磷脂或植物油；所述植物油较佳地为熔点在35℃以下的植物油，更佳地为熔点在20℃以下的植物油；所述植物油更佳地为大豆油；
    其中，所述脂类物质较佳地为磷脂和植物油的组合，所述脂类物质更佳地为卵磷脂 和植物油的组合或者卵磷脂和大豆油的组合。
  15. 如权利要求13或14所述的脂性药物制剂，其特征在于，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述磷脂在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、7％-25％或4％-25％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-25％，所述卵磷脂在所述脂性药物制剂中的质量百分比为50％-85％或者50％-77％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-50％、6％-45％、7％-25％或4％-25％；
    其中，较佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为15％-21％或者17％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为65％-82％或者70％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为6％-12％或者8％-10％；
    或者，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述磷脂在所述脂性药物制剂中的质量百分比为40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-12％，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-75％，所述大豆油在所述脂性药物制剂中的质量百分比为20％-50％；
    或者，所述脂性药物制剂包括如下组分：利多卡因、磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述磷脂在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8％-40％；
    其中，较佳地，所述脂性药物制剂包括如下组分：利多卡因、卵磷脂和大豆油，所述利多卡因在所述脂性药物制剂中的质量百分比为3％-15％，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-80％，所述大豆油在所述脂性药物制剂中的质量百分比为8％-50％或8％-40％。
  16. 如权利要求13-15任一项所述的脂性药物制剂，其特征在于，所述脂性药物制剂含有抑菌成分；所述抑菌成分较佳地为氯己定、抗菌素和磺胺类药物中的一种或多种，更佳地为氯己定；其中，所述氯己定在所述脂性药物制剂中的质量比较佳地为0.1％-5％， 更佳地为0.2％-2％。
  17. 一种脂性药物制剂，其特征在于，所述脂性药物制剂包括利多卡因、磷脂、植物油和氯己定；所述利多卡因在所述脂性药物制剂中的质量百分比为2％-25％，所述磷脂在所述脂性药物制剂中的质量百分比为40％-82％或者40％-80％，所述植物油在所述脂性药物制剂中的质量百分比为15％-40％，所述氯己定在所述脂性药物制剂中的质量比为0.1％-5％；所述植物油较佳地为大豆油；所述氯己定在所述脂性药物制剂中的质量比较佳地为0.2％-2％；所述脂性药物制剂中各组分的质量百分比之和为100％；
    或者，所述脂性药物制剂包括利多卡因、卵磷脂、植物油和氯己定；所述利多卡因在所述脂性药物制剂中的质量百分比为2％-25％，所述卵磷脂在所述脂性药物制剂中的质量百分比为40％-82％或者40％-80％，所述植物油在所述脂性药物制剂中的质量百分比为15％-40％，所述氯己定在所述脂性药物制剂中的质量比为0.1％-5％；所述植物油较佳地为大豆油；所述氯己定在所述脂性药物制剂中的质量比较佳地为0.2％-2％；所述脂性药物制剂中各组分的质量百分比之和为100％；
    其中，较佳地，所述利多卡因在所述脂性药物制剂中的质量百分比为2％-21％或者2％-20％，所述磷脂为卵磷脂，并且在所述脂性药物制剂中的质量百分比为40％-82％或者50％-70％，所述植物油在所述脂性药物制剂中的质量百分比为6％-40％、15％-50％或者15％-40％，所述氯己定在所述脂性药物制剂中的质量比为0.2％-2％；所述脂性药物制剂中各组分的质量百分比之和为100％。
  18. 一种脂性药物制剂在制备治疗开放性人体表面疼痛或者开放性人体组织表面疼痛的药物中的应用，其特征在于，所述脂性药物制剂为如权利要求1-17任一项所述的脂性药物制剂；所述开放性人体表面疼痛或者所述开放性人体组织表面疼痛较佳地为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术后的手术后切口疼痛；
    较佳地，将所述脂性药物制剂以小于或等于0.5克所述脂性药物制剂/公斤体重的剂量应用于所述开放性人体表面疼痛处后能够使得血药浓度峰值小于5000ng/mL或不高于2500ng/mL；
    和/或，所述开放性人体表面疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛，所述应用于所述开放性人体表面疼痛处指的是将所述脂性药物制剂涂抹在所述开放性人体表面疼痛处；或者，所述开放性人体表面疼痛为非肛肠手术后的手术后切口疼痛，所述应用于所述开放性人体表面疼痛处指的是将所述脂性药物制剂埋入所述手术后切口。
  19. 一种采用脂性药物制剂的镇痛方法，所述脂性药物制剂为如权利要求1-17任一项所述的脂性药物制剂；所述镇痛方法包括如下步骤：
    将所述脂性药物制剂施用并维持在开放性人体表面即可；或者，将所述脂性药物制剂维持在开放性人体组织表面即可；
    较佳地，所述开放性人体表面疼痛或者开放性人体组织表面疼痛为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术后的手术后切口疼痛；
    较佳地，当治疗的疼痛为非肛肠手术后的手术后切口疼痛时，所述镇痛方法包括如下步骤：将所述脂性药物制剂施放在未缝合或部分未缝合的手术切口中；或者，当治疗的疼痛为非肛肠手术后的手术后切口疼痛时，所述治疗方法包括如下步骤：将所述脂性药物制剂注射或放入进入手术切口或手术切口附近的组织中；
    较佳地，当治疗的疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛时，所述镇痛方法包括如下步骤：将所述脂性药物制剂涂抹并维持在所述开放性人体表面或所述开放性人体组织表面上。
  20. 一种采用如权利要求1-17任一项中所述的脂性药物制剂的治疗方法，所述治疗方法用于治疗开放性人体组织表面疼痛；
    其中，所述开放性人体组织表面疼痛较佳地为烧伤疼痛、烧伤去痂时的疼痛、肛肠手术后的切口和创面的疼痛或非肛肠手术后的手术后切口疼痛；
    较佳地，将如权利要求1-17任一项中所述的脂性药物制剂以小于或等于0.5克所述脂性药物制剂/公斤体重的剂量应用于所述开放性人体组织表面疼痛处后能够使得血药浓度峰值小于5000ng/mL或不高于2500ng/mL；
    和/或，当所述开放性人体组织表面疼痛为烧伤疼痛、烧伤去痂时的疼痛或肛肠手术后的切口和创面的疼痛时，较佳地，所述应用于所述开放性人体组织表面疼痛处的方法指的是将所述脂性药物制剂涂抹在所述开放性人体组织表面疼痛处；或者，当所述开放性人体表面组织疼痛为非肛肠手术后的手术后切口疼痛时，较佳地，所述应用于所述开放性人体表面组织疼痛处的方法指的是将所述脂性药物制剂埋入所述手术后切口。
PCT/CN2020/084832 2019-04-15 2020-04-15 脂性药物制剂及其应用 WO2020211762A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US17/603,015 US20220193014A1 (en) 2019-04-15 2020-04-15 Lipid pharmaceutical preparation and application thereof
EP20792218.8A EP3957328A4 (en) 2019-04-15 2020-04-15 LIPID PHARMACEUTICAL PREPARATION AND ASSOCIATED APPLICATION
CN202080021973.7A CN113597316B (zh) 2019-04-15 2020-04-15 脂性药物制剂及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910299949.9A CN111840553A (zh) 2019-04-15 2019-04-15 脂性药物制剂及其应用
CN201910299949.9 2019-04-15

Publications (1)

Publication Number Publication Date
WO2020211762A1 true WO2020211762A1 (zh) 2020-10-22

Family

ID=72838033

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/084832 WO2020211762A1 (zh) 2019-04-15 2020-04-15 脂性药物制剂及其应用

Country Status (4)

Country Link
US (1) US20220193014A1 (zh)
EP (1) EP3957328A4 (zh)
CN (2) CN111840553A (zh)
WO (1) WO2020211762A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992483B2 (en) 2021-03-31 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111840553A (zh) * 2019-04-15 2020-10-30 湖州依诺唯新药物制剂有限公司 脂性药物制剂及其应用
CN114344299A (zh) * 2021-12-17 2022-04-15 佐建锋 一种具有长效缓释作用的脂质释药系统及其制备方法
CN115252557B (zh) * 2022-09-01 2023-06-02 广东嘉博制药有限公司 一种罗哌卡因多囊脂质体制剂的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4647586A (en) * 1984-08-10 1987-03-03 Lederle (Japan), Ltd. Pharmaceutical oil-in-water type micro-emulsion
CN1152873A (zh) * 1994-07-12 1997-06-25 阿斯特拉公司 治疗疼痛的新型药物制剂
WO2003077885A2 (en) * 2002-03-12 2003-09-25 Neurogesx, Inc. Free-base formulations of local anesthetics
CN101027065A (zh) * 2004-06-15 2007-08-29 陈献 磷脂组合物及其制备和使用方法
CN101636148A (zh) * 2006-12-12 2010-01-27 埃德加·乔尔·阿科斯塔-扎拉 基于连接剂的卵磷脂微型乳剂输送载体
CN108354903A (zh) * 2018-04-11 2018-08-03 西安力邦生物医药技术有限公司 一种局部麻醉镇痛缓释递药系统及其制备方法和应用
CN108379269A (zh) * 2018-04-20 2018-08-10 武汉百纳礼康生物制药有限公司 一种用于术后镇痛的缓释制剂及其制备方法

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5227165A (en) * 1989-11-13 1993-07-13 Nova Pharmaceutical Corporation Liposphere delivery systems for local anesthetics
SE9200762D0 (sv) * 1992-03-12 1992-03-12 Astra Ab New topical use
ATE183092T1 (de) * 1995-10-28 1999-08-15 Braun Melsungen Ag Lokalanästhetika und/oder zentralanalgetika enthaltende pharmazeutische zusammensetzungen
KR100343125B1 (ko) * 1999-09-14 2002-07-05 임정옥 도포용 리포좀형 혼합국소마취제 및 그 제조방법
US20060127429A1 (en) * 2004-12-13 2006-06-15 Mccartt Mary D Topical numbing composition for laser therapy
US20080207560A1 (en) * 2005-01-07 2008-08-28 Ayako Harada Composition For External Use
US9012477B2 (en) * 2009-01-06 2015-04-21 Nuvo Research Inc. Method of treating neuropathic pain
CN101904814A (zh) * 2009-06-04 2010-12-08 上海恒瑞医药有限公司 制备载药乳剂的方法
CN102933200B (zh) * 2009-12-18 2015-11-25 莱迪杜德制药公司 包含磷脂的单相凝胶组合物
US20140066481A1 (en) * 2010-04-01 2014-03-06 Pharmanest Ab Water-Free Pharmaceutical Compositions Suitable for Local Anaesthetics
SG184071A1 (en) * 2010-04-01 2012-10-30 Pharmanest Ab Thermogelling anaesthetic compositions
CN102370619A (zh) * 2010-08-18 2012-03-14 罗和国 脂肪乳乳化局麻药
AR082287A1 (es) * 2011-07-19 2012-11-28 Zars Pharma Inc Una formulacion anestesica local formadora de solido
CN103705439B (zh) * 2012-09-28 2017-11-28 上海恒瑞医药有限公司 脂质凝胶药物制剂及其制备方法和用途
CN103705442B (zh) * 2012-09-28 2017-12-01 上海恒瑞医药有限公司 原位脂质凝胶药物制剂及其制备方法和用途
CN103142458B (zh) * 2013-01-22 2015-09-09 莱普德制药有限公司 无成瘾性镇痛缓释递药系统的组方与制备方法
CN106943340A (zh) * 2017-04-28 2017-07-14 北京茗泽中和药物研究有限公司 一种盐酸利多卡因凝胶
CN108159055A (zh) * 2018-01-04 2018-06-15 西安力邦医药科技有限责任公司 治疗乳腺癌的长效递药系统、其制备方法及应用
CN108743952B (zh) * 2018-06-11 2021-08-31 西安力邦医药科技有限责任公司 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法
CN109316602A (zh) * 2018-11-13 2019-02-12 西安力邦医药科技有限责任公司 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用
CN111840553A (zh) * 2019-04-15 2020-10-30 湖州依诺唯新药物制剂有限公司 脂性药物制剂及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4647586A (en) * 1984-08-10 1987-03-03 Lederle (Japan), Ltd. Pharmaceutical oil-in-water type micro-emulsion
CN1152873A (zh) * 1994-07-12 1997-06-25 阿斯特拉公司 治疗疼痛的新型药物制剂
WO2003077885A2 (en) * 2002-03-12 2003-09-25 Neurogesx, Inc. Free-base formulations of local anesthetics
CN101027065A (zh) * 2004-06-15 2007-08-29 陈献 磷脂组合物及其制备和使用方法
CN101636148A (zh) * 2006-12-12 2010-01-27 埃德加·乔尔·阿科斯塔-扎拉 基于连接剂的卵磷脂微型乳剂输送载体
CN108354903A (zh) * 2018-04-11 2018-08-03 西安力邦生物医药技术有限公司 一种局部麻醉镇痛缓释递药系统及其制备方法和应用
CN108379269A (zh) * 2018-04-20 2018-08-10 武汉百纳礼康生物制药有限公司 一种用于术后镇痛的缓释制剂及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3957328A4
YUKO IKEDA ET AL.: "Pharmacokinetics of Lidocaine, Bupivacaine, and Levobupivacaine in Plasma and Brain in Awake Rats", ; ANESTHESIOLOGY, vol. 112, 2010, pages 1396 - 1403

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992483B2 (en) 2021-03-31 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics

Also Published As

Publication number Publication date
US20220193014A1 (en) 2022-06-23
EP3957328A1 (en) 2022-02-23
CN111840553A (zh) 2020-10-30
CN113597316B (zh) 2023-11-24
CN113597316A (zh) 2021-11-02
EP3957328A4 (en) 2023-03-22

Similar Documents

Publication Publication Date Title
WO2020211762A1 (zh) 脂性药物制剂及其应用
KR101716793B1 (ko) 무중독성 진통 서방형 약물전달시스템 및 이의 제조방법
EP1809329B1 (en) Sustained local anesthetic composition containing saib
KR101792200B1 (ko) 열감응성 겔 마취제 조성물
US9427416B2 (en) Composition and method for treating hemorrhoids and/or anorectal disorders
Gokten et al. Efficacy of levobupivacaine infiltration to nephrosthomy tract in combination with intravenous paracetamol on postoperative analgesia in percutaneous nephrolithotomy patients
JP2010531298A (ja) 疼痛を治療するための局所用組成物
US12064404B2 (en) Topical formulations and treatments
WO2019141178A1 (zh) 药物组合物、贴剂及其制备方法、镇痛方法、应用
RU2530605C2 (ru) Композиция для инъекций, содержащая гидроксихлорохин, для местного применения при лечении геморроя
WO2018147790A1 (en) Anaesthetic composition comprising ropivacaine, prilocaine and lidocaine
EP1884241B1 (en) A oral preparation comprising dyclonine hydrochloride
JPH072659A (ja) 抗アレルギー貼付剤
RU2286781C2 (ru) Способ лечения химических ожогов пищевода у детей
JP3782551B2 (ja) 鎮痛組成物
US20230000772A1 (en) Opioid independent surgical anesthetic
US20240299618A1 (en) Means and methods for wound healing
JP7450916B2 (ja) 表面麻酔剤
EP4052697A1 (en) Opioid independent surgical anesthetic
Jooma Liposuction and anaesthesia
WO2014204416A1 (en) A solution used in the treatment of hemorrhoid
CN113616796A (zh) 一种止痛抗炎复方缓释制剂
CN109276718A (zh) 含亚甲蓝注射液的组合封闭液及其应用
TW201828941A (zh) 一種點鼻劑或噴鼻劑組合物
안재상 Feasibility Study of Sub-Tenons Anesthesia for Phacoemulsification in Dogs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20792218

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020792218

Country of ref document: EP

Effective date: 20211115