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WO2013146386A1 - Préparation d'anesthésique local à libération prolongée - Google Patents

Préparation d'anesthésique local à libération prolongée Download PDF

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Publication number
WO2013146386A1
WO2013146386A1 PCT/JP2013/057520 JP2013057520W WO2013146386A1 WO 2013146386 A1 WO2013146386 A1 WO 2013146386A1 JP 2013057520 W JP2013057520 W JP 2013057520W WO 2013146386 A1 WO2013146386 A1 WO 2013146386A1
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Prior art keywords
liposome
local anesthetic
sustained
release preparation
aqueous phase
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2013/057520
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English (en)
Japanese (ja)
Inventor
昌樹 海堀
吉朗 荒木
雅憲 權
誠二 伊藤
恵子 山下
直紀 大友
辰一 徳江
京子 田口
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KANSAI MEDICAL UNIVERSITY EDUCATIONAL Corp
Terumo Corp
Original Assignee
KANSAI MEDICAL UNIVERSITY EDUCATIONAL Corp
Terumo Corp
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Publication of WO2013146386A1 publication Critical patent/WO2013146386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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 relates to a local anesthetic sustained sustained release preparation.
  • Non-Patent Document 1 Non-Patent Document 1
  • the organic solvent is used in the preparation process, so that it is essential to remove the organic solvent (for example, Patent Documents 1 and 2), and the point that inflammation is caused because the acid locally increases with decomposition. It is an issue.
  • Non-patent document 2 Multivesicular liposomes (MVL) have been developed as lipid-based sustained-release drug carriers for local or systemic drug delivery (Patent Documents 1 and 2). The sustained release time is not enough.
  • An object of the present invention is to provide a sustained-release preparation for sustained release of a local anesthetic having excellent durability for a composition of liposomes carrying a local anesthetic.
  • a first liposome having an outer membrane formed of a plurality of lipid bilayer membranes;
  • a plurality of second liposomes having an outer membrane formed of a plurality of lipid bilayer membranes housed in an inner region of the first liposome defined by the outer membrane;
  • a second liposome inner region defined by the outer membrane of the second liposome;
  • An ionic gradient is formed at least between the interior region of the second liposome and the exterior of the first liposome;
  • a local anesthetic sustained-release preparation comprising a local anesthetic within at least the second liposome inner region.
  • the local anesthetic sustained sustained release preparation according to the above 1, having a viscosity at 25 ° C.
  • the local anesthetic sustained sustained release preparation according to any one of 1 to 5 above which is administered to at least one selected from the group consisting of subcutaneous, fascia and intramuscularly over the surgical wound site and / or its adjacent site. 7.
  • the local anesthetic sustained sustained release preparation according to any one of 1 to 6 above which can be administered using a syringe having a 19-33 gauge needle. 8).
  • Drug sustained sustained release formulation is at least one aminoamide type anesthetic selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine and salts thereof.
  • the local anesthetic sustained-release preparation of the present invention has excellent persistence. Therefore, the local anesthetic sustained-release preparation of the present invention can relieve pain due to postoperative period for a sufficient period.
  • FIG. 1 shows a transmission electron microscope (TEM) showing a cross section of a liposome after a drug is introduced into the liposome composition produced by the same method as the liposome composition used in the sustained-release preparation for local anesthetic of the present invention. (Magnification: 32000 times).
  • FIG. 2 is a graph showing the relationship between the concentration of the total lipid constituting the first liposome and the second liposome and the viscosity of the local anesthetic sustained sustained release preparation, which the local anesthetic sustained sustained release preparation of the present invention has. It is.
  • FIG. 3 is a graph showing the analgesic effect of the bupivacaine sustained release preparation.
  • FIG. 4 is a graph showing the volume dependency of the analgesic effect of the bupivacaine sustained release preparation.
  • FIG. 5 is a graph showing the analgesic effect of bupivacaine alone and an empty preparation.
  • the local anesthetic sustained sustained release formulation of the present invention is A first liposome having an outer membrane formed of a plurality of lipid bilayer membranes; A plurality of second liposomes having an outer membrane formed of a plurality of lipid bilayer membranes housed in an inner region of the first liposome defined by the outer membrane; A second liposome inner region defined by an outer membrane of the second liposome, and an ion gradient is formed at least between the second liposome inner region and the outside of the first liposome, A local anesthetic sustained sustained release formulation comprising an anesthetic within at least the second liposome internal region.
  • the local anesthetic sustained-release preparation of the present invention has a first liposome, a first liposome inner region, a second liposome in the first liposome, and a second liposome inner region, thereby providing a local anesthetic. Can be sustainedly released. Therefore, the local anesthetic sustained-release preparation of the present invention can relieve pain after a sufficient period of time. In this invention, it is said that it is excellent in sustainability that a local anesthetic can be sustained-released continuously.
  • a composition containing the first liposome and the second liposome before introduction of the local anesthetic (which may include an external liquid) is referred to as a “liposome composition”.
  • the liposome composition after introducing a local anesthetic into the internal region of the liposome or the internal region of the second liposome and the first liposome is referred to as “local anesthetic sustained sustained release preparation”.
  • the local anesthetic sustained-release preparation of the present invention further has an ion gradient formed between at least the second liposome inner region and the first liposome outer region, whereby the second liposome inner region or second The drug retention ability in the liposome and the first liposome internal region is increased, and the durability is further improved.
  • the local anesthetic moves along the ion gradient from the outside of the first liposome to the inside of the first liposome, and further to the inside of the second liposome.
  • the drug can be introduced into the liposome and a clinically sufficient effective concentration can be maintained in the liposome.
  • the liposome composition used for the local anesthetic sustained-release preparation of the present invention has a first liposome having an outer membrane formed of a plurality of lipid bilayers and a first defined by the outer membrane.
  • a plurality of second liposomes having an outer membrane formed of a plurality of lipid bilayer membranes, and a second liposome inner region defined by the outer membrane of the second liposome. And including a local anesthetic within at least the second liposome interior region.
  • a plurality of the first liposomes can be used in the local anesthetic sustained-release preparation.
  • the first liposome has a plurality of first liposome inner regions defined by the outer membrane and a plurality of outer membranes formed of a plurality of lipid bilayers contained in the first liposome inner region.
  • the second liposome has a second liposome inner region defined by the outer membrane of the second liposome.
  • the local anesthetic sustained-release preparation of the present invention has a first liposome, a first liposome inner region, a second liposome in the first liposome, and a second liposome inner region, thereby providing local anesthesia.
  • the drug can be sustained and sustained, and is suitable for administration by at least one method selected from the group consisting of injection, infiltration, application and implantation. In the present invention, the injection includes local injection. The same applies to infiltration and application.
  • Phospholipids which are main lipids, are main components of biological membranes, and generally include a hydrophobic group composed of a long-chain alkyl group and a hydrophilic group composed of a phosphate group in the molecule. It is an amphiphilic substance.
  • HSPC hydrogenated soybean phosphatidylcholine
  • HSPC hydrogenated egg yolk phosphatidylcholine
  • Liposomes constituting the local anesthetic sustained-release preparation of the present invention may contain other membrane components in addition to the above main components, such as lipids other than phospholipids or derivatives thereof, membrane stabilizers, oxidation An inhibitor or the like can be included as necessary.
  • Lipids other than phospholipids are lipids that have a hydrophobic group such as a long-chain alkyl group in the molecule and do not contain a phosphate group in the molecule, and are not particularly limited, but include glyceroglycolipid, sphingoglycolipid, cholesterol And sterol derivatives such as these and derivatives such as hydrogenated products thereof.
  • cholesterol derivatives examples include sterols having a cyclopentanohydrophenanthrene ring.
  • the liposome which comprises the local-anesthetic sustainable sustained release formulation of this invention contains cholesterol.
  • the antioxidant examples include ascorbic acid, uric acid or a tocopherol homologue, that is, vitamin E. There are four isomers of ⁇ , ⁇ , ⁇ , and ⁇ in tocopherol, and any of them can be used in the present invention.
  • the lipid bilayer composition of the liposome constituting the local anesthetic sustained-release preparation of the present invention is preferably 100 to 50 mol% of phospholipid and 0 to 50 mol% of cholesterol, more preferably 70 to 50 mol of phospholipid. % And cholesterol 30-50 mol%.
  • the outer diameter of the first liposome is preferably 1 ⁇ m or more in view of excellent sustained release performance, suppressing the diffusion of the liposome from the administration site, and staying at the administration site without moving into the blood vessel. .
  • the outer diameter of the first liposome is preferably 1 to 20 ⁇ m, and more preferably 3 to 10 ⁇ m.
  • the plurality of second liposomes are each independently (one second liposome is non-concentric with another second liposome) in the first liposome internal region (inner aqueous phase). Exists.
  • the second liposome is closed by an outer membrane formed by a plurality of lipid bilayer membranes.
  • the first liposome is closed by including the second liposome inside by an outer membrane formed of a plurality of lipid bilayer membranes.
  • the plurality of second liposomes contained in the first liposome are not in contact with each other, or are not aggregated and fixed even if in contact.
  • the second liposome contained in the first liposome is not in contact with the inner surface of the membrane of the first liposome, or is not fixed even if it is in contact.
  • a plurality of second liposomes exist in the inner aqueous phase of the first liposome, and in this state, between the outer surfaces of the plurality of second liposomes or the inner surface of the first liposome and the second liposome.
  • the layer structure of the multi-layered lipid bilayer constituting the outer shape of the first liposome is not particularly limited, but is preferably 30 to 70 layers.
  • the first liposome has an internal region that houses the second liposome.
  • the outer diameter of the second liposome is not particularly limited, but is preferably 100 to 800 nm from the viewpoint of excellent local anesthetic entrapment amount and sustained release performance.
  • the number of second liposomes is not particularly limited, but it is preferably 8 to 40 in the internal region of the first liposome of one liposome particle.
  • the layer structure of the multi-layer lipid bilayer constituting the outer shape of the second liposome is preferably 1 to 10 layers from the outer diameter of the second liposome.
  • an ionic gradient is formed at least between the second liposome internal region (inner aqueous phase) and the outside of the first liposome. It is preferable from the viewpoint of enhancing the holding ability and being superior in sustainability.
  • the term “ion” simply means an ion that forms the ion gradient.
  • an ion gradient is formed between the second liposome inner region and the outside of the first liposome. (1) The inside of the second liposome is sandwiched between the outer membranes of the second liposome.
  • the ion concentration in the first liposome inner region is a value between the ion concentration in the second liposome inner region and the ion concentration outside the first liposome.
  • the ion gradient preferably has the highest ion concentration in the second liposome internal region from the viewpoint of introducing a large amount of local anesthetic.
  • the ion concentration in the second liposome inner region (pH 2.0 to 3.5)> the ion concentration in the first liposome inner region (pH 4.0 to 5.5)> the ion concentration outside the first liposome ( pH 6.0-7.5).
  • a proton gradient pH gradient
  • a high ion concentration corresponds to a low pH. That is, in this case, the pH of the second liposome inner region is preferably the lowest.
  • ion gradient method an ion gradient is formed at least between the second liposome internal region and the outside of the first liposome, and a local anesthetic added to the outside of the first liposome follows the ion gradient to form a liposome membrane.
  • the local anesthetic is encapsulated inside the liposome by permeating and the proton gradient (pH gradient) is preferable as the ion gradient.
  • the ion gradient method empty liposomes in which a local anesthetic is not encapsulated are produced in the second liposome inner region and the first liposome inner region, and the local anesthetic is added to the external solution of the first liposome.
  • An empty liposome is formed of an inner region of a first liposome having an outer membrane formed of a plurality of lipid bilayer membranes and a plurality of lipid bilayer membranes accommodated in the inner region of the first liposome. It means a liposome that does not contain a drug (before the drug is encapsulated) in the second liposome internal region having a formed outer membrane.
  • the local anesthetic sustained-release preparation of the present invention can encapsulate the local anesthetic in liposomes by an ion gradient method.
  • the pH gradient method using a pH gradient as the ion gradient is most preferably applied.
  • liposomes are formed using an acidic pH buffer solution (for example, a citric acid solution having a pH of 2 to 3) as the first inner aqueous phase and / or the second inner aqueous phase, and then the first liposome.
  • the inside of the second liposome and the first liposome is lower, and the outside of the first liposome has a higher pH gradient. It can be set as the form to form.
  • a pH gradient can also be formed via an ammonium ion gradient.
  • the local anesthetic will be described below.
  • the local anesthetic contained in the local anesthetic sustained-release preparation of the present invention is not particularly limited as long as it is generally used as a local anesthetic.
  • One preferred embodiment is that the local anesthetic can be encapsulated in the liposome by an ion gradient method.
  • the local anesthetic is preferably ionizable amphiphilic, and more preferably amphiphilic weakly basic.
  • Examples of local anesthetics include aminoamide type anesthetics such as bupivacaine, ropivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine and salts thereof; and ester type anesthetics such as cocaine, procaine, tetracaine and salts thereof.
  • aminoamide type anesthetics are preferable, and bubivacine, ropivacaine, levobubicaine or a salt thereof is more preferable.
  • Other examples include opioid analgesics such as morphine, fentanyl, and codeine.
  • the local anesthetic sustained sustained release formulation of the present invention can include an effective amount of a local anesthetic.
  • the amount of the local anesthetic contained in the local anesthetic sustained-release preparation of the present invention is not particularly limited and can be appropriately adjusted according to the use. Specifically, for example, when the local anesthetic sustained-release preparation of the present invention is administered once to a human, it can contain an amount capable of continuously relieving pain for at least 3 days. For example, when the local anesthetic sustained-release preparation of the present invention is administered once, the amount of the local anesthetic contained in the local anesthetic sustained-release preparation of the present invention is 200 mg or less per kg of human body weight. The effective amount is continuously released at the surgical site over at least 3 days.
  • Dosing once not only means that the total amount of local anesthetic required is administered to one site, but also the required amount is administered to the surgical wound and / or adjacent sites over several sites. It also means.
  • the upper dose limit is limited by the toxicity of individual local anesthetics.
  • the lower limit is that the local anesthetic present in the first liposome internal region and / or the second liposome internal region may be released to the administration site at the minimum amount necessary for slow pain, There is no particular limitation because it varies depending on the size of the wound. Also, the exact dose will vary depending on the characteristics of the individual anesthetic and patient factors such as age, gender, weight and physical condition.
  • the upper limit of the effective amount of bupivacaine or a salt thereof can be 25 mg / kg human body weight.
  • the upper limit of the effective amount of ropivacaine or a salt thereof can be 40 mg / kg human body weight.
  • the upper limit of the effective amount of levobupivacaine or a salt thereof can be 30 mg / kg human body weight.
  • the upper limit of the effective amount of lidocaine or a salt thereof can be 140 mg / kg human body weight.
  • the upper limit of the effective amount of mepivacaine or a salt thereof can be 140 mg / kg human body weight.
  • the upper limit of the effective amount of prilocaine or a salt thereof can be 200 mg / kg human body weight.
  • the sustained-release preparation for sustained release of local anesthetic of the present invention is sustainedly released for at least 3 days or 4 days or more in a single administration, the effective amount is in a sustained period (3 days or more, or 4 to 7 days). The amount to be released slowly. Therefore, the amount of local anesthetic contained in one administration of the local anesthetic sustained sustained release preparation of the present invention is the effective amount per kg of human body weight and 3 days or more, or 4 to 7 days. It can be the amount multiplied by the release period.
  • the amount of the local anesthetic contained in the local anesthetic sustained-release preparation of the present invention is the molar ratio of the total lipid contained in the liposome composition used in the local anesthetic sustained-release preparation of the present invention [local Anesthetic (mol) / total lipid (mol)] is preferably 0.05 or more, and can be 0.06 to 0.20.
  • the local anesthetic is contained in at least the second liposome internal region. From the viewpoint that the local anesthetic can be sustainedly released more continuously and the dosage of the local anesthetic sustained sustained release preparation can be reduced, a local anesthetic is further added to the internal region of the first liposome other than the second liposome. It is preferable to include.
  • the local anesthetic contained in the second liposome inner region and the local anesthetic contained in the first liposome inner region other than the second liposome may be the same or different. It is mentioned as one of the preferable embodiments that the local anesthetics contained in both of the above locations are the same.
  • the shape and outer diameter of the first liposome and the shape and outer diameter of the second liposome are almost the same and do not change.
  • the ion gradient in the liposome composition is maintained unless the outer membrane of the first or second liposome is destroyed.
  • the local anesthetic sustained sustained release preparation of the present invention is to remain at the administration site, prevent the local anesthetic-encapsulated liposomes from moving into the blood, and more gradually release the local anesthetic at the administration site.
  • the viscosity is preferably 4 to 1000 cP, more preferably 30 to 600 cP, and still more preferably 60 to 400 cP.
  • the local anesthetic sustained-release preparation of the present invention is to remain at the administration site, prevent the local anesthetic-encapsulated liposomes from moving into the blood, and to release the local anesthetic more sustainedly at the administration site.
  • the concentration of the total lipid constituting the first liposome and the second liposome in the local anesthetic sustained-release preparation is preferably 8 to 50 (w / v%). (W / v%) is more preferable, 25 to 45 (w / v%) is more preferable, and 30 to 36 (w / v%) is particularly preferable.
  • the viscosity of the local anesthetic sustained-release preparation of the present invention can be increased. It can be set as the said range.
  • the local anesthetic sustained-release preparation of the present invention can be used alone or in combination of two or more.
  • the method for using the local anesthetic sustained-release preparation of the present invention is not particularly limited.
  • it can be administered by at least one method selected from the group consisting of injection, infiltration, application and implantation.
  • the injection, infiltration, application, and implantation methods are not particularly limited. These include being local. Examples include intramuscular injection, subcutaneous injection; subcutaneous infiltration; spray application; and sheet embedding.
  • administering the local anesthetic sustained-release preparation of the present invention by injection it can be administered using a syringe having a 19-33 gauge (G) injection needle, and the thickness of the injection needle is appropriately selected. Can do. It is preferable to select the gauge of the injection needle as appropriate depending on the place and method of injection.
  • a relatively thick needle for example, in the case of slow and reliable injection into the muscle, it is preferable to administer a relatively thick needle, and 19 to 25 gauge. Preferably there is.
  • administration should be carried out with a relatively thin needle, preferably 27 to 33 gauge.
  • the sustained-release sustained-release preparation of the local anesthetic of the present invention can be used when the lipid concentration and viscosity of the liposome are high and / or by appropriately selecting the average particle size of the first liposome independently or in combination. Infiltration administration is possible using a relatively thin injection needle without affecting the excellent sustained release of the drug, and it has a great effect in that pain during administration can be reduced.
  • a surgical wound and / or an adjacent part thereof As a part to which the local anesthetic sustained-release preparation of the present invention is applied, for example, a surgical wound and / or an adjacent part thereof can be mentioned.
  • the types of surgery in the surgical wound area include, for example, gastrectomy, hepatectomy, appendectomy, caesarean section, cholecystectomy, hysterectomy, colectomy, prostatectomy, discectomy, ovariectomy , Orthopedic surgery, coronary artery bypass grafting, debridement and the like.
  • the adjacent part is not particularly limited as long as it is in contact with and / or close to the surgical wound.
  • the local anesthetic sustained-release preparation of the present invention can be administered to at least one selected from the group consisting of subcutaneous, fascia, and intramuscularly over the surgical wound site and / or its adjacent site.
  • the method for administering the sustained-release preparation for local anesthetic of the present invention comprises a method for administering a sustained-release preparation for local anesthetic along the surgical wound after closing the fascia of the surgical site having an incision to be sutured. There are a step of administering to the membrane and / or muscle below it with a needle, and a step of closing the skin after administration to the fascia and / or muscle.
  • a step of uniformly administering a local anesthetic subcutaneously at a plurality of locations at a position near the suture along the sutured incision and a position surrounding the incision may be included.
  • the administration site does not need to be one site, and is preferably administered over several sites so that the sustained-release preparation for local anesthetics can be uniformly administered along the surgical wound.
  • the injection needle is preferably punctured perpendicularly or obliquely to the skin so that the tip approaches the sutured incision.
  • a device equipped with the operator's hand or a pressure sensor can be used to check between the subcutaneous expansions on the skin. By confirming the feeling of swelling, it can be confirmed that the local anesthetic sustained-release agent is firmly administered to the tissue and is uniformly diffused to the surgical wound site.
  • the use of the local anesthetic sustained sustained release preparation of the present invention can provide an analgesic period of at least about 3 days or more after administration, and preferably has an analgesic period of 4 to 7 days, more preferably 4 to 5 days. Can bring.
  • a liposome composition containing at least a first liposome having an outer membrane formed of a plurality of lipid bilayer membranes is produced.
  • a method of introducing a local anesthetic into the liposome by a driving force by an ion gradient can be mentioned.
  • a method for producing a liposome composition for example, Preparing a first emulsion by mixing a water-miscible solvent containing a lipid with a first inner aqueous phase solution containing a compound for forming an ionic gradient at a volume ratio of 0.7 to 2.5; , Mixing the second inner aqueous phase solution with the first emulsion at a volume ratio of 0.7 or more to prepare a second emulsion;
  • One preferred embodiment includes the step of substituting the outer aqueous phase of the second emulsion with an aqueous solution having a lower compound concentration for forming the ion gradient than the first inner aqueous phase solution.
  • the ion gradient is preferably a proton concentration gradient.
  • the first inner aqueous phase solution used in the step of preparing the first emulsion contains a compound for forming an ion gradient.
  • a compound for forming an ion gradient one of them.
  • protons are preferable as described above.
  • the compound for forming an ion gradient include compounds that ionize to generate protons, ammonium ions, and protonated amino groups.
  • sulfates such as ammonium sulfate, dextran sulfate and chondroitin sulfate; hydroxides; phosphoric acid, glucuronic acid, citric acid, carbonic acid, hydrogen carbonate, nitric acid, cyanic acid, acetic acid, benzoic acid, and salts thereof; Halides such as bromide and chloride; inorganic or organic anions; anionic polymers.
  • the local anesthetic When the local anesthetic is encapsulated in the internal aqueous phase of the liposome (at least the second internal region of the liposome) by the pH gradient method, the local anesthetic is protonated by the protons present in the internal aqueous phase and is charged. As a result, the local anesthetic is prevented from diffusing out of the liposome, and the local anesthetic is retained in the aqueous phase in the liposome.
  • an anion such as a sulfate ion is generated together with an ion (cation) that forms an ion gradient such as a proton, but the weakly basic local anesthetic in which the anion is protonated
  • the local anesthetic can be stably held in the inner aqueous phase. That is, a compound for forming an ion gradient can generate a counter ion (anion) for a basic local anesthetic capable of forming a salt or complex with the basic local anesthetic by ionization.
  • Such a counter ion is not particularly limited as long as it is a pharmaceutically acceptable anion, but sulfate ion is most preferable.
  • Ammonium sulfate is generally used as a compound that generates sulfate ions, but it can also be selected from dextran sulfate, chondroitin sulfate, and the like.
  • Other counter ions include hydroxide, phosphate, glucuronate, citrate, carbonate, bicarbonate, nitrate, cyanate, acetate, benzoate, bromide, chloride, and Examples include anions generated by ionization from other inorganic or organic anions or anionic polymers.
  • the concentration of the compound for forming an ion gradient in the first inner aqueous phase solution is preferably 50 to 500 mM, and more preferably 100 to 300 mM.
  • the solvent used in preparing the lipid-containing solution in the step of preparing the first emulsion is a water-miscible solvent.
  • the water-miscible solvent refers to a solvent that can dissolve the phospholipid and other membrane components used in the production of the sustained-release preparation for local anesthetic of the present invention and is miscible with water.
  • the water-miscible solvent include ethanol, methanol, isopropyl alcohol, and butanol.
  • Solvents that are not miscible with water are not used in the present invention.
  • water-immiscible solvents such as water-immiscible organic solvents such as chloroform
  • the resulting liposome does not have a form in which a plurality of small liposomes and a first inner aqueous phase are accommodated in a large liposome, but is merely like expanded polystyrene.
  • individual liposomes are aggregated (so-called multivesicular liposome, MVL).
  • the liposomes (multivesicular vesicles) thus obtained are fixed to each other so that the outer membranes of a plurality of relatively small diameter liposomes (vesicles) cannot be separated.
  • the plurality of liposomes to which the outer membrane is fixed are not independent of each other. So-called multivesicular liposomes are structurally different from the liposomes used in the present invention in the above respects.
  • the amount of lipid as the liposome raw material is preferably 20 to 100% by mass, more preferably 20 to 60% by mass of the water-miscible solvent.
  • the components other than the components that can constitute the lipid bilayer fill the inner region of the second liposome. be able to.
  • a part of a second inner aqueous phase solution described later may be mixed in the inner region of the second liposome.
  • the method for preparing the first emulsion is not particularly limited, and a conventionally known method can be used.
  • the pH of the inner aqueous phase (the first and / or second liposome inner region) can be adjusted as appropriate.
  • citric acid is used as the compound for forming an ion gradient in the first inner aqueous phase solution
  • the difference in pH between the inner aqueous phase and the outer aqueous phase is preferably 3 or more.
  • ammonium sulfate is used, a pH gradient is formed by chemical equilibrium, so there is no need to previously adjust the pH of the inner aqueous phase solution.
  • the water-miscible solvent containing lipid and the first inner aqueous phase solution added thereto are in a volume ratio (first inner aqueous phase solution / water miscible solvent). It can be 0.7 to 2.5, and 1.0 to 2.0 is preferable.
  • the second inner phase used in the step of adding the first inner aqueous phase solution to the water-miscible solvent containing lipid to prepare the first emulsion and then adding the second inner aqueous phase solution to the first emulsion.
  • the inner aqueous phase solution is not particularly limited.
  • the same solution as the first inner aqueous phase a HEPES solution or NaCl solution, and an aqueous saccharide solution such as glucose and sucrose can be mentioned, and the same solution as the first inner aqueous phase is preferable.
  • the first inner aqueous phase and the second inner aqueous phase are both aqueous ammonium sulfate solutions.
  • components other than the components that can form the lipid bilayer can fill the inner region of the first liposome (except for the second liposome).
  • the inner region of the first liposome (except for the second liposome) may contain a part of the first emulsion.
  • the method for preparing the second emulsion is not particularly limited, and a conventionally known method can be used.
  • the method for producing a sustained-release preparation for sustained release of a local anesthetic of the present invention comprises a step of replacing the outer aqueous phase of the second emulsion with an aqueous solution having a lower compound concentration for forming an ionic gradient than the first inner aqueous phase solution. .
  • the outer aqueous phase of the first liposome after preparing the second emulsion is at least from the liposome second inner aqueous phase solution or a mixed solution containing the liposome first inner aqueous phase solution and the liposome second inner aqueous phase solution.
  • an ion gradient is formed at least between the inner region of the second liposome and the outer portion of the first liposome.
  • the water-miscible solvent is removed from the liposome composition system, and the resulting liposome can be given the form that the local anesthetic sustained-release preparation of the present invention has.
  • an outer aqueous phase for substitution used in the method for producing a sustained-release sustained-release preparation for local anesthetic of the present invention an aqueous solution having a lower compound concentration for forming an ion gradient than at least the first inner aqueous phase solution is used.
  • a HEPES solution an aqueous saccharide solution such as glucose or sucrose, or a citric acid solution is used. It is desirable that the pH of the outer aqueous phase is adjusted by a buffering agent, and it is preferable that the pH is adjusted in the range of 5.5 to 8.5 in consideration of lipid degradation and pH difference during in vivo administration. More preferably, the pH is in the range of 6.0 to 7.5.
  • the osmotic pressure of the inner aqueous phase and the outer aqueous phase of the liposome is not particularly limited as long as it is adjusted to an osmotic pressure within a range where the liposome is not destroyed by the difference in osmotic pressure between the two, but physical stability of the liposome is not limited. Considering the characteristics, the smaller the osmotic pressure difference is, the more desirable.
  • One preferred embodiment of the outer aqueous phase for replacement is an aqueous solution having a lower compound concentration for forming an ion gradient than the first inner aqueous phase solution and the second inner aqueous phase solution.
  • the method for producing a sustained-release preparation for sustained release of a local anesthetic of the present invention includes a step of introducing a local anesthetic into the liposome composition by a driving force due to the ion gradient.
  • the step of introducing the local anesthetic into the liposome contained in the liposome composition by the driving force by the ion gradient for example, the local anesthetic is dissolved in water or the like, and the obtained local anesthetic solution is obtained.
  • the local anesthetic is dissolved in water or the like, and the obtained local anesthetic solution is obtained.
  • the phase transition temperature of the liposome membrane eg, 65 ° C or higher.
  • a liposome encapsulating a local anesthetic (local anesthetic sustained-release preparation of the present invention) can be produced.
  • Each component used when manufacturing the local-anesthetic sustainable sustained release formulation of this invention can be used individually or in combination of 2 types or more, respectively.
  • HSPC hydrogenated soybean phosphatidylcholine (molecular weight 790, Lipoid SPC3)
  • DMPC Dimyristoylphosphatidylcholine (molecular weight 677.9, NOF Corporation)
  • Chol cholesterol (molecular weight 388.66, manufactured by Solvay)
  • Bupivacaine hydrochloride molecular weight 324.89, JINAN CHENGHUI-SHUANGDA Chemical Co. Itd
  • Ropivacaine hydrochloride molecular weight 310.88, JINAN CHENGHUI-SHUANGDA Chemical Co. Itd)
  • the pH of the liposome internal region was lowered to 2.0 to 3.5, and the internal region A pH gradient is formed between the outer region and the outer region.
  • ⁇ Local anesthetic introduction by pH gradient> The liposomes after ion gradient formation were quantified for HSPC and cholesterol to determine the total lipid concentration. Based on the calculated total lipid concentration, the amount of bupivacaine hydrochloride as the local anesthetic is calculated so that the local anesthetic / total lipid (mol / mol) ratio is 0.3, and the necessary amount of local anesthetic is added. After weighing, a 10 mg / mL local anesthetic solution was prepared with RO water. A predetermined amount of a local anesthetic solution preheated to 65 ° C. was added to the liposome solution heated at 65 ° C., and then the local anesthetic was introduced by heating and stirring at 65 ° C. for 60 minutes. The liposome after introduction of the local anesthetic was ice-cooled promptly.
  • Preparation Example 2 Bupivacaine hydrochloride-containing sustained release formulation 2
  • Sustained-release preparation (Bupivacaine-containing sustained-release preparation 2) was produced.
  • Preparation Example 3 Bupivacaine hydrochloride-containing sustained release preparation 3
  • the local anesthetic sustained sustained release preparation (prepared in the same manner as in Preparation Example 1 except that the ratio of the charged amount of local anesthetic in preparation example 1 (local anesthetic / total lipid (mol / mol)) ratio was changed to 0.4 A bupivacaine-containing sustained release formulation 3) was produced.
  • Preparation Example 4 ropivacaine hydrochloride-containing sustained release preparation 4
  • a local anesthetic sustained-release preparation (Ropivacaine hydrochloride-containing sustained-release preparation 4) was produced in the same manner as Preparation Example 1 except that the drug of Preparation Example 1 was changed to ropivacaine hydrochloride.
  • the preparation drug amount (local anesthetic / total lipid (mol / mol)) ratio of the local anesthetic was set to 0.4.
  • FIG. 2 is a graph showing the relationship between the concentration of the total lipid constituting the first liposome and the second liposome and the viscosity of the local anesthetic sustained sustained release preparation, which the local anesthetic sustained sustained release preparation of the present invention has. It is.
  • the vertical axis of the graph represents the viscosity (unit: cP) of the local anesthetic sustained-release preparation
  • the horizontal axis of the graph represents the concentration (unit) of total lipid constituting the first liposome and the second liposome. : Mg / mL).
  • the rightmost data is Preparation Example 1
  • the second from the right is Preparation Example 3
  • the third from the right is Preparation Example 2
  • the fourth from the right is the sustained growth rate of each local anesthetic.
  • a release formulation is a local anesthetic continuous sustained release preparation suitably manufactured by the method according to manufacture example 1.
  • the viscosity of the preparation markedly increased as the lipid concentration in the sustained-release preparation for local anesthetic of the present invention increased.
  • the viscosity suddenly increased when the lipid concentration of the preparation exceeded 300 (mg / mL).
  • the viscosity was 200 mg / mL or less
  • the viscosity was relatively low
  • the lipid concentration was 100 mg / mL or less
  • ⁇ Liposome concentration of liposome in local anesthetic sustained-release preparation Phospholipid concentration (mg / mL): Phospholipid concentration in the liposome suspension quantified using high performance liquid chromatography or phospholipid quantification. Cholesterol concentration (mg / mL): Cholesterol concentration in a liposome suspension quantified using high performance liquid chromatography. Total lipid concentration (mol / L): Total molar concentration (mM) of lipid as a membrane constituent calculated from the above phospholipid concentration and cholesterol concentration.
  • Local anesthetic concentration (mg / mL): After diluting the liposome composition with RO water (reverse osmosis membrane water) so that the total lipid concentration of the preparation obtained above is about 20-30 mg / mL, was further diluted 20 times with methanol to disrupt the liposomes. In this solution, the absorbance at 263 nm was quantified by high performance liquid chromatography using an ultraviolet absorptiometer. The concentration of the encapsulated local anesthetic is shown as local anesthetic amount (mg) / total preparation amount (mL).
  • RO water reverse osmosis membrane water
  • Local anesthetic carrying amount (local anesthetic / total lipid molar ratio):
  • the local anesthetic concentration contained in the liposome is determined from the ratio of the local anesthetic concentration to the total lipid concentration, and the local anesthetic / total lipid mole ratio. Shown as a ratio.
  • Average particle diameter ( ⁇ m) The average particle diameter of the first liposome in the local anesthetic sustained-release preparation as measured with a light scattering diffraction particle size distribution analyzer Beckman Coulter LS230.
  • Von Frey filament was performed every day before surgery, 10 hours after surgery, and 14 days later. Specifically, a von Frey Hair set (made by North Coast Medical, trade name: Touch-Test), which requires a predetermined stress to bend, is applied to the surgical part of the rat from under the gauge net containing the rat. On the other hand, the stress (threshold for mechanical stimulation) when the rat was surprised and raised the foot was determined.
  • Touch-Test North Coast Medical, trade name: Touch-Test
  • Example 1 [Continuous analgesic preparation in the surgical wound area]
  • Example 1 Using the above-mentioned rat postoperative pain model, the analgesic effect of the above-mentioned bupivacaine-containing sustained release preparations 1 and 2 was evaluated using von Frey filament as described above.
  • a prescribed amount (0.42 mg as bupivacaine amount) of bupivacaine-containing sustained-release preparation 1 or 2 is used in the vicinity of the plantar muscle, respectively, using an insulin syringe (Thermomyjector 27G). Injected into. The result is shown in FIG. In FIG.
  • the threshold was significantly increased at all time points from 10 hours after the operation to the 6th day after the operation compared to the incision only group. It was. A significant difference between the bupivacaine-containing sustained-release preparation of the present invention and the sham operation group (incision only group) means that post-operative pain is predominantly suppressed until the sixth day after the operation. Should be noted.
  • the threshold value was significantly increased compared to the incision alone group at all time points from 10 hours after surgery to 4 days after surgery. It was.
  • the postoperative pain was suppressed predominately until the 4th day after the operation. From the 9th day onward, the difference between the sustained-release preparation of the present invention and the sham operation group (incision only group) is considered to be due to the healing of the incision. From the above, it has been clarified that the bupivacaine-containing sustained release preparation of the present invention can provide a postoperative analgesic effect for about one week by administering once to a surgical wound after surgery. It is considered that the local anesthetic sustained-release preparation of the present invention can provide a very long analgesic effect to humans by administering once to a surgical wound after surgery.
  • Example 2 Using the above-mentioned rat postoperative pain model, the volume dependence due to the analgesic effect of the above-mentioned bupivacaine-containing sustained release preparation 3 was evaluated using von Frey filament as described above.
  • For the postoperative pain model of rats after suturing use bupivacaine-containing sustained-release preparation 3 with a syringe for insulin (Thermomyjector 27G) and give prescribed amounts (bupivacaine amounts of 0.32 and 0.63 mg) near the plantar muscles, respectively. Injected into. The result is shown in FIG. In FIG. 4, three bar graphs are shown before pre-incision, 10 hours after the operation, and every 1 to 14 days after the operation.
  • the left white bar graph shows the results of the postoperative pain model with only incision
  • the central diagonal bar graph shows the bupivacaine-containing sustained release preparation 3 as bupivacaine amount.
  • the results of using 32 mg for the postoperative pain model are shown
  • the right bar graph shows the results of using bupivacaine-containing sustained-release preparation 3 as the amount of bupivacaine at 0.63 mg for the postoperative pain model.
  • the medium volume 0.32 mg / body injection group showed a significant increase in threshold from the incision only group from 10 hours after surgery to 4 days after surgery.
  • the threshold value was significantly increased compared with the incision alone group at all time points from 10 hours after surgery to 7 days after surgery.
  • the local anesthetic sustained sustained release preparation containing bupivacaine of the present invention has an extremely excellent postoperative pain suppression effect, and can be seen to be volume dependent in both pain threshold and duration. It was.
  • the local anesthetic sustained sustained release preparation of the present invention is considered to be dose-dependent for humans in both pain threshold and duration as well.
  • FIG. 1 shows a transmission electron microscope (TEM) showing a cross section of a liposome after a drug is introduced into the liposome composition produced by the same method as the liposome composition used in the sustained-release preparation for local anesthetic of the present invention. (Magnification: 32000 times).
  • the liposome shown in FIG. 1 is divided almost at the center of the liposome.
  • the liposome 1 shown in FIG. 1 is accommodated in a first liposome 5 having an outer membrane 3 formed of a plurality of lipid bilayers, and a first liposome inner region 7 defined by the outer membrane 3.
  • the outer diameter of the first liposome 5 is about 7 ⁇ m
  • the outer diameter of the second liposome 9 is 100 to 800 nm.
  • the liposome composition after introduction of the drug used for the photography of FIG. 1 was produced in the same manner as the liposome composition used for the local anesthetic sustained-release preparation of the present invention. Therefore, the local anesthetic sustained-release preparation of the present invention is considered to have the same form as the liposome of FIG.
  • a predetermined amount of a DNP solution preheated to 65 ° C. was added to the liposome solution preheated at 65 ° C., and then the drug was introduced by heating and stirring at 65 ° C. for 60 minutes.
  • the liposome after drug introduction was quickly ice-cooled.
  • ⁇ Removal of unencapsulated drug> 20 mM HEPES / 0.9% sodium chloride solution (pH 7.5) was added and dispersed in the liposome after introduction of the drug, and the liposome was precipitated by centrifugation at 3500 rpm for 15 minutes.

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CN107055863A (zh) * 2017-01-23 2017-08-18 烟台金正环保科技有限公司 一种碟管式反渗透处理柠檬酸废水的工艺
CN111182889A (zh) * 2017-08-28 2020-05-19 美商Tlc生物医药公司 缓释麻醉剂组成物及其制备方法
WO2020259670A1 (fr) * 2019-06-28 2020-12-30 江苏恒瑞医药股份有限公司 Composition lipidique à libération prolongée et son procédé de préparation
JP2021517890A (ja) * 2018-03-30 2021-07-29 ティーエルシー バイオファーマシューティカルズ、インク． 徐放性麻酔剤組成物およびその調製方法
JP2022523208A (ja) * 2019-02-26 2022-04-21 ティーエルシー バイオファーマシューティカルズ、インク． 疼痛の治療に使用するための医薬組成物
CN114668723A (zh) * 2020-12-25 2022-06-28 江苏恒瑞医药股份有限公司 一种含有局部麻醉药的脂质体及其制备方法
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CN107055863A (zh) * 2017-01-23 2017-08-18 烟台金正环保科技有限公司 一种碟管式反渗透处理柠檬酸废水的工艺
CN111182889A (zh) * 2017-08-28 2020-05-19 美商Tlc生物医药公司 缓释麻醉剂组成物及其制备方法
JP2021517890A (ja) * 2018-03-30 2021-07-29 ティーエルシー バイオファーマシューティカルズ、インク． 徐放性麻酔剤組成物およびその調製方法
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JP2022523208A (ja) * 2019-02-26 2022-04-21 ティーエルシー バイオファーマシューティカルズ、インク． 疼痛の治療に使用するための医薬組成物
WO2020259670A1 (fr) * 2019-06-28 2020-12-30 江苏恒瑞医药股份有限公司 Composition lipidique à libération prolongée et son procédé de préparation
CN114668723A (zh) * 2020-12-25 2022-06-28 江苏恒瑞医药股份有限公司 一种含有局部麻醉药的脂质体及其制备方法

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