CN110934868A - Insoluble compound, pharmaceutical composition and application thereof - Google Patents
Insoluble compound, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN110934868A CN110934868A CN201811113051.XA CN201811113051A CN110934868A CN 110934868 A CN110934868 A CN 110934868A CN 201811113051 A CN201811113051 A CN 201811113051A CN 110934868 A CN110934868 A CN 110934868A
- Authority
- CN
- China
- Prior art keywords
- levobupivacaine
- solvate
- water
- pamoic acid
- pharmaceutical composition
- 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.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 title description 15
- 208000004550 Postoperative Pain Diseases 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 4
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical class CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 claims description 101
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 62
- 239000012453 solvate Substances 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 26
- 239000000725 suspension Substances 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003125 aqueous solvent Substances 0.000 claims description 7
- 238000010255 intramuscular injection Methods 0.000 claims description 4
- 239000007927 intramuscular injection Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
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- 238000001356 surgical procedure Methods 0.000 abstract description 2
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- 238000002360 preparation method Methods 0.000 description 52
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- 239000012065 filter cake Substances 0.000 description 21
- SIEYLFHKZGLBNX-NTISSMGPSA-N levobupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-NTISSMGPSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 238000002347 injection Methods 0.000 description 20
- 239000007924 injection Substances 0.000 description 20
- 229960001464 levobupivacaine hydrochloride Drugs 0.000 description 20
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- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 238000004090 dissolution Methods 0.000 description 15
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- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 7
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- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 6
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- 229930006000 Sucrose Natural products 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 6
- 239000000945 filler Substances 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 229960003150 bupivacaine Drugs 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- YGLLICRFEVEWOZ-UHFFFAOYSA-L disodium;3-carboxy-1-[(3-carboxy-2-oxidonaphthalen-1-yl)methyl]naphthalen-2-olate Chemical compound [Na+].[Na+].C1=CC=C2C(CC3=C4C=CC=CC4=CC(=C3O)C([O-])=O)=C(O)C(C([O-])=O)=CC2=C1 YGLLICRFEVEWOZ-UHFFFAOYSA-L 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 238000004537 pulping Methods 0.000 description 5
- 150000003254 radicals Chemical group 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- BKVAAWMQOQLENB-UHFFFAOYSA-N 15-hydroxy stearic acid Chemical compound CCCC(O)CCCCCCCCCCCCCC(O)=O BKVAAWMQOQLENB-UHFFFAOYSA-N 0.000 description 4
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 4
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
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- 208000002193 Pain Diseases 0.000 description 4
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- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- 150000002148 esters Chemical class 0.000 description 4
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 3
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- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The present invention provides poorly soluble complexes of formula (I), pharmaceutical compositions and the use of said pharmaceutical compositions for the prevention or treatment of surgery, intra-operative and post-operative pain. According to the technical scheme of the invention, the medicine which is simple in production process and can stably release local anesthetic in vivo for a long time is provided, can be released for more than three days continuously, not only can prolong the analgesic effect of postoperative pain, but also can be convenient for doctors and patients to use, and has good medication compliance.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a slightly soluble compound, a medicinal composition (namely a long-acting solid particle suspension injection) and medical application of the medicinal composition.
Background
1-butyl-N- (2, 6-xylyl) -2-piperidine formamide hydrochloride (bupivacaine hydrochloride for short) is a local anesthetic, and is widely used for local anesthesia in operation and postoperative analgesia in the global range. It is administered as an injection for local infiltration anesthesia, peripheral nerve block and intravertebral block. Bupivacaine is a racemic mixture of levorotatory isomer and dextrorotatory isomer in a ratio of 1:1, and the curative effect mainly comes from the levorotatory isomer, and the toxicity mainly comes from the dextrorotatory isomer. Based on the requirement for higher safety, Levobupivacaine Hydrochloride (Levobupivacaine Hydrochloride) is also widely used for local infiltration anesthesia, peripheral nerve block and intraspinal block, and is sold in China market.
Postoperative pain is acute pain that occurs immediately after surgery (usually lasting no more than 7 days), and is by nature acute nociceptive pain, and is the most common and urgent clinical acute pain to manage. If not sufficiently controlled in the initial state, it is likely to develop into postoperative chronic pain. Clinically, opioid drugs are frequently used for treating postoperative pain, but have adverse reactions such as respiratory depression and addiction. Local anesthetics are also the most clinically important analgesic drugs, including procaine, lidocaine, tetracaine, bupivacaine, ropivacaine, but the effective action time of the existing local anesthetics is relatively short (usually lasting less than 7 hours). Therefore, clinically, the continuous incision analgesic device is used for instilling the amide local anesthetic on the wound so as to maintain a certain treatment concentration. However, this device still has certain disadvantages, such as: the medicine storage bag must be carried about, which brings inconvenience to patients; the infiltration catheter is placed in the body to increase local irritation and have certain complications; the infiltration catheter is not easy to take out after the treatment is finished, etc. The development of long-acting local anesthetics is therefore a focus of research today.
Because the effective action time of the existing local anesthetic is relatively short, in order to prolong the lasting action time of the water-soluble medicine, various new technologies are applied to try to prolong the action time. A successful example is the bupivacaine liposome injection suspension (trade name: Lima) developed using multilamellar liposomes as carrier material
) The externally applied preparation is widely used for relieving various postoperative pains, can generate a remarkable analgesic effect for 72 hours after being injected to an operation part by a single preparation, and has the remarkable defect that the production process is complicated because the Exparel adopts a complicated liposome preparation technology.
Therefore, a drug which has a simple production process, can stably release local anesthetic in vivo for a long time, can be continuously released for at least more than three days, can prolong the analgesic effect of postoperative pain, is convenient for doctors and patients to use, and has good medication compliance is needed.
Disclosure of Invention
The invention discloses a slightly soluble compound or a solvate thereof, and also discloses a pharmaceutical composition containing the slightly soluble compound or the solvate thereof, namely a long-acting solid particle suspension injection.
The preparation using the indissolvable compound or the solvate thereof can continuously release the medicine in vivo, maintain the concentration of the medicine effect for more than 24 hours, and achieve the analgesic effect of pain for more than 24 hours after operation.
According to one aspect of the invention there is provided a complex of formula (I) or a solvate thereof:
wherein the configuration of the chiral atom is S configuration.
Preferably, the complex is a solvate-free.
Preferably, the complex, or solvate thereof, has an X-ray powder diffraction pattern expressed in degrees 2 Θ substantially as shown in figure 1.
Preferably, the complex or solvate thereof is in an amorphous state.
Preferably, the median particle diameter D of the complex or solvate thereof50The value is in the range of 0.1 to 50 μm.
According to another aspect of the present invention, there is provided a process for preparing the poorly soluble complex or solvate thereof as described above, characterized by mixing a water-soluble levobupivacaine salt and a water-soluble pamoic acid salt in an aqueous solvent selected from methanol, ethanol, acetone, dimethyl sulfoxide, N-dimethylformamide, water or a mixed solvent of one or more thereof.
Preferably, in the above preparation method, the molar ratio of the levobupivacaine salt to the pamoate salt is 2:1 to 3: 1.
Preferably, in the above production method, the production is carried out in a pure water solvent or a mixed solvent containing more than 90% by volume of water.
Preferably, in the above preparation method, levobupivacaine hydrochloride and pamoate disodium are mixed for preparation.
According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a complex as described above or a solvate thereof and a pharmaceutically acceptable excipient.
Preferably, the pharmaceutically acceptable excipients comprise one or more of the following: suspending agent, surfactant, bulking agent, antiseptic, isotonic regulator, pH regulator, buffer and water.
Preferably, the poorly soluble complex or solvate thereof has a median particle diameter D50Solid particles having a value in the range of 0.2 to 20 μm.
Preferably, the pharmaceutical composition is a suspension and comprises 1 to 300mg, preferably 5 to 100mg, of the complex or solvate thereof in 1mL of the suspension.
Preferably, the pharmaceutical composition is free of water and comprises greater than or equal to 10 wt%, preferably greater than or equal to 20 wt% of the complex or solvate thereof.
Preferably, the suspending agent is selected from one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably one or more of sodium carboxymethyl cellulose and polyvinylpyrrolidone; the surfactant is selected from one or more of polysorbate 20 (Tween-20), polysorbate 40 (Tween-40), polysorbate 60 (Tween-60), polysorbate 65 (Tween-65), polysorbate 80 (Tween-80), polysorbate 85 (Tween-85), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188, poloxamer 407 and the like), and 15-hydroxystearic acid polyethylene glycol ester, preferably one or more of Tween-20, Tween-80, 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188; the filler is selected from one or more of mannitol, sucrose, maltose, xylitol, lactose, glucose, starch, sorbitol or analogues thereof, preferably one or more of mannitol, lactose and sucrose; the preservative is selected from one or more of benzoic acid, benzyl alcohol, butylated hydroxytoluene, chlorobutanol, gallate, hydroxybenzoate, ethylene diamine tetraacetic acid and salts thereof, phenol, chlorocresol, m-cresol, benzethonium chloride, myristyl-gamma-methylpyridine chloride, mercury phenylacetate and thimerosal, and preferably one or more of benzyl alcohol and hydroxybenzoate; the isotonic regulator is selected from one or more of mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose and lactose, preferably one or more of mannitol, sodium chloride and glucose; the buffer is selected from one or more of phosphate, acetate, citrate or tris buffer, preferably phosphate.
According to another aspect of the present invention, there is provided the use of a pharmaceutical composition as described above for the prevention or treatment of surgical, intra-operative and post-operative pain.
Preferably, in the above application, the pharmaceutical composition is administered by subcutaneous, intradermal or intramuscular injection.
According to the technical scheme of the invention, the medicine which is simple in production process and can stably release local anesthetic in vivo for a long time is provided, can be released for more than three days continuously, not only can prolong the analgesic effect of postoperative pain, but also can be convenient for doctors and patients to use, and has good medication compliance.
Drawings
In the following, the attached drawings are provided to describe in detail embodiments according to the present invention, in which:
FIG. 1 shows a powder diffraction contrast diagram of bis (levobupivacaine) pamoic acid obtained by different preparation methods.
Figure 2 shows X-ray diffraction patterns of levobupivacaine, pamoic acid and bis (levobupivacaine) pamoic acid in comparison.
FIG. 3 shows a TGA-DTA plot of bis (levobupivacaine) pamoic acid.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments. It will be appreciated that other embodiments are contemplated and may be made without departing from the scope or spirit of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense.
Unless otherwise indicated, all numbers expressing feature sizes, quantities, and physical and chemical characteristics used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached claims are approximations that can be suitably varied by those skilled in the art in seeking to obtain the desired properties utilizing the teachings disclosed herein. The use of numerical ranges by endpoints includes all numbers within that range and any range within that range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, and the like.
The poorly soluble complexes of the invention have a structure and composition according to formula (i).
The configuration of the chiral atom in the formula (I) is S configuration, the base part is levobupivacaine, and the acid radical part is pamoic acid.
The slightly soluble complex has stable molecular composition ratio, the molar ratio of the levobupivacaine to the pamoic acid is 2:1, and the slightly soluble complex is defined as the bis (levobupivacaine) pamoic acid.
The complex of the present invention is a solid which is bonded by non-covalent bond such as ionic bond, hydrogen bond, van der waals force, pi-pi stacking effect, etc., and may be in the form of a salt or a eutectic. It has properties that are physically, chemically, mechanically, and substantially different from the individual components or simple mixtures thereof. For the definition of the co-crystals and salts, reference may be made to Journal of China pharmaceutical university 2012, 43(5): 475-.
The indissolvable property means that the solubility of the bis (levobupivacaine) pamoic acid or the solvate thereof in pure water or 0.01M Phosphate Buffered Saline (0.01M Phosphate Buffered Saline) with pH7.4 is less than 0.01g/ml calculated by levobupivacaine.
It is known in the art that levobupivacaine is a single chiral isomer of bupivacaine, it is known in the art that it contains a small amount of dexbupivacaine, and that levobupivacaine and dexbupivacaine relative ratios above 10:1 can be considered levobupivacaine.
The bis (levobupivacaine) pamoic acid provided by the invention can exist in a form of solvate or exist in a form of solvate, wherein the solvent of the solvate is selected from one or more of methanol, acetone, ethanol and water, and is preferably free of solvate.
The bis (levobupivacaine) pamoic acid and the solvate thereof provided by the invention are crystalline powder or amorphous powder, preferably amorphous powder.
The X-ray powder diffraction pattern of the solid powder of the bis (levobupivacaine) pamoic acid and the solvate thereof expressed by the angle of 2 theta is basically as shown in the attached figure 1.
The X-ray powder diffraction pattern of the compound provided by the invention is measured by a DX-27mini diffractometer (Dandonghao element). The measurement parameters comprise the wavelength of 1.5406 angstroms (Cu/kappa α 1), step measurement, step length of 0.02 degrees, an initial angle of 4 degrees, a termination angle of 40 degrees, a scanning speed of 1.0 second/step, a tube voltage of 35KV and a tube current of 15 mA.
It is well known to those skilled in the art that for diffractograms containing diffraction peaks, diffraction peak position errors within ± 0.2 ° for 2 θ values are acceptable; in addition, the peak identification of the X-ray powder diffraction pattern caused by sample preparation, instrument difference and software processing also has difference, such as the number of peaks is more or less, and if the number of peaks is not more than 20%, the peaks are generally regarded as the same crystal form. Similarly, for a powder diffraction pattern with a small number of diffraction peaks and a diffuse shape (broad peaks or steamed bread peaks), the geometrical topological properties of the diffuse diffraction peaks are consistent and generally considered to be the same crystalline state.
It is understood by those skilled in the art that single crystalline, mixed crystalline or amorphous forms of crystalline powders comprising different crystalline, amorphous forms are also disclosed.
The invention provides a method for preparing bis (levobupivacaine) pamoic acid or a solvate thereof in an aqueous solvent system, which is prepared by mixing a water-soluble levobupivacaine salt and a water-soluble pamoic acid salt in an aqueous solvent.
The aqueous solvent is pure water or a mixed solvent of water and an organic solvent, wherein the volume ratio of the water in the mixed solvent is more than 10%. The organic solvent is a solvent which can be mutually dissolved with water in any ratio, such as methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-dimethylformamide and N-methylpyrrolidone. The present invention is preferably prepared in a pure water solvent or a mixed solvent containing more than 90% by volume of water, and more preferably in pure water.
The levobupivacaine salt refers to a salt formed by levobupivacaine and inorganic acid or organic acid, wherein the inorganic acid comprises but is not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid and phosphoric acid; organic acids include, but are not limited to, formic, acetic, trifluoroacetic, propionic, lactic, succinic, maleic, fumaric, tartaric, citric, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, benzoic, ascorbic, or salicylic acid. A typical example of a levobupivacaine salt is levobupivacaine hydrochloride.
The pamoate is a divalent carboxylate formed by pamoate radical and metal ions or organic amine positive ions, wherein the metal ions include but are not limited to sodium, potassium, lithium, calcium, magnesium, zinc and aluminum; organic amine cations include, but are not limited to, ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, dicyclohexylamine, tributylamine, tetrahydropyrrole, pyrrole, imidazole, pyrazole, pyridine, piperidine, piperazine, morpholine, meglumine, and cations of amino acids such as arginine, lysine and protons. Typical examples of pamoic acid salts are disodium pamoate and dipotassium pamoate.
The water-solubility refers to that the solubility of levobupivacaine salt or pamoate in pure water at room temperature is more than or equal to 0.01 g/ml;
the levobupivacaine salt or the pamoic acid salt used in the preparation method provided by the invention can be a pure chemical product or a product prepared in situ, for example, levobupivacaine free alkali is suspended in water, a proper amount of inorganic acid or organic acid is added to form a salt and is dissolved in the water to prepare a corresponding water-soluble levobupivacaine salt, similarly, pamoic acid which is difficult to dissolve in the water is suspended in the water, and a proper amount of alkaline substance such as sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate and ammonia water is added to form a salt and is dissolved in the water to prepare the water-soluble pamoic acid salt in situ.
In the preparation method provided by the invention, in order to stably obtain the 2:1 salt, the molar ratio of the levobupivacaine salt to the pamoate salt is more than 2.0, and preferably 2:1 to 3: 1.
The bis (levobupivacaine) pamoic acid or the solvate thereof prepared by the preparation method provided by the invention is precipitated from an aqueous solvent in a solid form, and an excessive levobupivacaine salt and a generated inorganic salt are remained in the solvent. Typical examples are the preparation of bis (levobupivacaine) pamoic acid by mixing levobupivacaine hydrochloride and disodium pamoate in an aqueous solution and precipitating out.
The invention preferably prepares solid powder from water, ethanol/water, methanol/water or acetone/water system, and more preferably prepares solid powder from water system. Median particle diameter D of solid powder50The values are expressed in the range of 0.1 to 50 μm, preferably 1 to 50 μm, more preferably 1 to 20 μm.
A simple physical mixture of levobupivacaine and pamoic acid showed two endothermic peaks in the differential thermal scan (DTA), consistent with those of the individual components of levobupivacaine or pamoic acid. The indissolvable compound provided by the invention has an endothermic peak which is inconsistent with an endothermic peak of a single component of levobupivacaine or pamoic acid or has no obvious endothermic peak.
The invention provides a method for measuring the solubility of bis (levobupivacaine) pamoic acid in simulated body fluid and ratio data of acid radicals and basic groups in suspension at different times, which are used for explaining the solubility and stability of the suspension of a difficult-soluble salt.
As will be appreciated by those skilled in the art, lower solubility may allow for longer lasting drug dissolution times for sustained drug release. It is released for at least 12 hours, preferably at least 24 hours, more preferably at least 48 hours, most preferably at least 72 hours.
The bis (levobupivacaine) pamoic acid provided by the invention has unexpected results, has very low solubility (saturated solubility of about 1.2mM in pH7.40.01MPBS), can stably exist in simulated body fluid medium, keeps the ratio of acid radical to base radical in solution stable (ratio 2:1), and is suitable for being prepared into solid suspension injection.
The invention provides a pharmaceutical composition containing bis (levobupivacaine) pamoic acid. It contains the bis (levobupivacaine) pamoic acid and pharmaceutically applicable auxiliary materials, and is released for at least 12 hours continuously, preferably at least 24 hours continuously, and more preferably at least 72 hours continuously.
The pharmaceutical composition may be a solid, an aqueous suspension, or a solid obtained by drying a suspension by an appropriate method. Suitable drying methods include freeze drying, spray drying or other drying methods.
The pharmaceutical composition is preferably an injectable composition, and can be an injection, and the injection can be used for subcutaneous, intradermal or intramuscular injection, and can slowly release bupivacaine in a local way to play the long-term analgesic effect.
The invention provides a double (levobupivacaine) pamoic acid injection, the physical form of the active ingredient exists in the form of solid particle suspension, and the double (levobupivacaine) pamoic acid injection can be prepared from any crystalline powder of the double (levobupivacaine) pamoic acid.
The particle diameter of solid particles in the double (levobupivacaine) pamoic acid injection provided by the invention is equal to the median particle diameter (D)50Value) is in the range of 0.2 to 50 μm, 0.2 to 20 μm, preferably 1 to 20 μm.
The bis (levobupivacaine) pamoic acid provided by the invention can be matched with a proper solvent and an additive commonly used in an injection and operated to prepare a corresponding injection composition for subcutaneous or intramuscular injection. The pharmaceutically applicable auxiliary materials are one or more of the following auxiliary materials (1) suspending agent, (2) surfactant, (3) filler, (4) preservative, (5) isotonic regulator, (6) pH regulator, (7) buffer and (8) water. The suspending agent is selected from one or more of carboxymethyl cellulose or sodium salt thereof, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably one or more of sodium carboxymethyl cellulose and polyvinylpyrrolidone; the surfactant is selected from one or more of polysorbate 20 (Tween-20), polysorbate 40 (Tween-40), polysorbate 60 (Tween-60), polysorbate 65 (Tween-65), polysorbate 80 (Tween-80), polysorbate 85 (Tween-85), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188, poloxamer 407 and the like), and 15-hydroxystearic acid polyethylene glycol ester, preferably one or more of Tween-20, Tween-80, 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188; the filler is selected from mannitol, sucrose, maltose, xylitol, lactose, glucose, starch, sorbitol or their analogues, preferably mannitol, lactose and sucrose; the preservative is selected from one or more of benzoic acid, benzyl alcohol, butylated hydroxytoluene, chlorobutanol, gallate, hydroxybenzoate, Ethylene Diamine Tetraacetic Acid (EDTA) and salts thereof, chlorocresol, m-cresol, benzethonium chloride, myristyl-gamma-methylpyridine chloride, mercury phenylacetate and thimerosal, and preferably one or more of benzyl alcohol and hydroxybenzoate; the isotonic regulator is selected from one or more of mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose and lactose, preferably one or more of mannitol, sodium chloride and glucose; the buffer is selected from one or more of phosphate, acetate, citrate or TRIS (hydroxymethyl) aminomethane (TRIS) buffer, preferably phosphate.
The injection composition provided by the invention comprises 1 to 300mg of bis (levobupivacaine) pamoic acid in 1ml of suspension, preferably 5 to 100mg of bis (levobupivacaine) pamoic acid in 1ml of suspension calculated by the total volume of the aqueous composition; or the weight percentage of each component calculated by the total weight of the composition without water is not less than 10 percent, and preferably not less than 20 percent.
The invention also provides a dissolution test and a result of the double (levobupivacaine) pamoic acid injection, which show that the double (levobupivacaine) pamoic acid injection has the characteristics of stable dissolution and drug sustained release.
The injection composition provided by the invention has an analgesic effect for not less than 12 hours, preferably not less than 24 hours, and more preferably not less than 72 hours.
In a preferred embodiment of the present invention, in vivo pharmacokinetic experiments and results of the injection of bis (levobupivacaine) pamoic acid are provided, demonstrating that the compounds of the present invention have a long-lasting sustained release profile over 72 hours.
Thus, the present invention also provides the use of bis (levobupivacaine) pamoic acid and injections thereof for the prevention or treatment of surgical, intra-operative and post-operative pain, preferably post-operative pain. Typical postoperative pain includes, but is not limited to, postoperative pain of surgical operations such as hemorrhoidectomy, colectomy, cystectomy, and the like.
Examples
The following examples are provided to aid in understanding the present disclosure, but are not intended to limit the same.
The drugs or agents used in the present invention are, unless otherwise specified, conventional commercially available products.
Bupivacaine (CAS #2180-92-9) used in the examples was purchased from Ji nan Rui xing pharmaceutical science, Inc.; levobupivacaine hydrochloride (CAS #: 27262-48-2) was purchased from Shandong platinum sources chemical Co., Ltd; pamoic acid was purchased from taizhou pioneer chemical ltd; pamoic acid disodium monohydrate was purchased from jonan shanbo biotechnology limited.
Unless otherwise stated, the 10% sulfuric acid, 10% nitric acid, 10% hydrobromic acid, 20% tartaric acid, 20% methanesulfonic acid, 10% sodium hydroxide solution, 10% sodium carbonate solution, and 5% ammonia water in the examples were prepared by diluting commercially available commercial products (solutions or solids) with purified water at a given concentration.
The high performance liquid chromatography conditions related to levobupivacaine are detected by the method below if no special description is provided. High performance liquid chromatography conditions:
HPLC-a, using octadecylsilane chemically bonded silica as filler, 250X 4.6mm, 5 μm, methanol as mobile phase A, 0.1% trifluoroacetic acid as mobile phase B, and eluting according to the following gradient with flow rate of 1.0ml/min, column temperature of 35 deg.C, and detection wavelength of 216 nm.
| Time/min | Mobile phase A (%) | Mobile phase B (%) |
| 0.01 | 55 | 45 |
| 10 | 55 | 45 |
| 14 | 90 | 10 |
| 23 | 90 | 10 |
| 30 | 55 | 45 |
| 35 | 55 | 45 |
| 36 | Stop |
HPLC-b, using octadecylsilane chemically bonded silica as filler, 250X 4.6mm, 5 μm, 10mmol/LpH2.5 phosphate buffer-acetonitrile (50: 50) as mobile phase, isocratic elution, flow rate of 1.0ml/min, column temperature of 40 deg.C, and detection wavelength of 216 nm.
HPLC-c uses octadecylsilane chemically bonded silica as filler, 250X 4.6mm, 5 μm, and uses potassium dihydrogen phosphate solution (2.72 g of potassium dihydrogen phosphate and 12.2g of sodium perchlorate, and 1000ml of water for dissolution), and uses phosphoric acid to adjust pH to 3.4) -acetonitrile 55:45 as mobile phase. The detection wavelength is 210 nm; the column temperature was 35 ℃; the flow rate was 1.0ml per minute.
Reference preparation example 1 preparation of levobupivacaine
Levobupivacaine hydrochloride (100g) was put into a reaction flask, and methylene chloride (500ml) and water (500ml) were added thereto and stirred to mix them uniformly. Then adding concentrated ammonia water into the reaction bottle to adjust the pH value to 10, and clarifying the system. After stirring for 1 hour, the layers were separated, the organic layer was washed with water (500ml 2 times), dried over anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was evaporated in vacuo at 45 ℃ to remove the solvent to give a white solid, levobupivacaine, weighing 80g, yield 90.3%.
Preparation example 1 preparation of bis (levobupivacaine) pamoic acid
7.2g of levobupivacaine hydrochloride (22mmol) are dissolved in 200ml of water and heated to 60 ℃. 4.5g of pamoate disodium monohydrate (10mmol) is dissolved in 40ml of water, and is added dropwise to the levobupivacaine hydrochloride aqueous solution under stirring, after the dropwise addition is finished, the temperature is kept at 60 ℃ and the stirring is continued for 1.5h, the hot filtration is carried out, the filter cake is leached for 50ml multiplied by 2 times, the filter cake is beaten and stirred by 200ml of water, the filtration and the pumping-out are carried out, the filter cake is dried at 60 ℃ overnight, and 9.1g of light yellow solid is obtained, and the yield is 94.3%. High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) confirmed a molar ratio of levobupivacaine to pamoic acid of 2: 1.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X-ray powder diffraction pattern is shown as amorphous, see CM156 of fig. 1.
Preparation example 2 preparation of bis (levobupivacaine) pamoic acid
71.5g levobupivacaine hydrochloride (0.22mol) are dissolved in 1450ml water and heated to 60 ℃. 45g of pamoic acid disodium monohydrate (0.1mol) is dissolved in 450ml of water, and is dripped into levobupivacaine hydrochloride water solution under stirring, after the dripping is finished, the temperature is kept at 60 ℃ and the stirring is continued for 0.5h, the hot filtering is carried out, 250ml of filter cake is leached for 2 times, the filter cake is beaten and stirred by 1000ml of water, the filtration and the pumping-out are carried out, the filter cake is dried at 60 ℃ overnight, 90g of light yellow solid is obtained, and the yield is 93.3%. High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) confirmed a molar ratio of levobupivacaine to pamoic acid of 2: 1. Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate of bis (levobupivacaine) pamoic acid, see figure 3.
The X-ray powder diffraction pattern is shown as amorphous, see CM163 of fig. 1. The X-ray powder diffraction pattern of the compound is compared with that of levobupivacaine (reference preparation example 1) and pamoic acid, and is shown in figure 2.
Preparation example 3 preparation of bis (levobupivacaine) pamoic acid
3.6g levobupivacaine hydrochloride (11mmol) dissolved in 190ml water, then 10ml ethanol, heating to 60 ℃. Dissolving 2.25g of pamoate disodium monohydrate (5mmol) in 30ml of water, dropwise adding the solution into levobupivacaine hydrochloride aqueous solution under stirring, continuously keeping the temperature of 60 ℃ and stirring for 0.5h after dropwise adding, filtering while hot, leaching a filter cake 30ml multiplied by 2 times, pulping the filter cake with 100ml of water and stirring, filtering, draining, and drying the filter cake by air blast at 60 ℃ overnight to obtain 4.2g of light yellow solid with the yield of 87.0%. High performance liquid chromatography (HPLC-a) and Nuclear Magnetic Resonance (NMR) analysis confirmed that the molar ratio of levobupivacaine and pamoic acid was 2:1 and no ethanol remained.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X-ray powder diffraction pattern shows a substantially amorphous state, see CM164 of fig. 1.
Preparation example 4 preparation of bis (levobupivacaine) pamoic acid
4.0g of levobupivacaine hydrochloride (12.3mmol) are dissolved in 200ml of water, 10ml of methanol are added and the mixture is heated to 50 ℃. Dissolving 2.25g of pamoate disodium monohydrate (5mmol) in 30ml of water, dropwise adding the solution into levobupivacaine hydrochloride aqueous solution under stirring, continuously keeping the temperature of 50 ℃ and stirring for 0.5h after dropwise adding, filtering while hot, leaching a filter cake 30ml multiplied by 2 times, pulping the filter cake with 100ml of water and stirring, filtering, draining, and drying the filter cake at 60 ℃ overnight to obtain 4.0g of light yellow solid with the yield of 82.9%. High performance liquid chromatography (HPLC-a) and Nuclear Magnetic Resonance (NMR) analysis confirmed that the molar ratio of levobupivacaine and pamoic acid was 2:1 and no methanol remained.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X-ray powder diffraction pattern shows a substantially amorphous state, see CM165 of figure 1.
Preparation example 5 preparation of bis (levobupivacaine) pamoic acid
The procedure was as in preparation example 4, with methanol being replaced by acetone, and the results were as in preparation example 4.
Preparation example 6 preparation of bis (levobupivacaine) pamoic acid
The procedure was as in preparation example 3, substituting ethanol for dimethyl sulfoxide, and the results were as in preparation example 3.
Preparation example 7 preparation of bis (levobupivacaine) pamoic acid
The procedure was as in preparation example 3 except that ethanol was replaced with N, N-dimethylformamide, and the results were as in preparation example 3.
Preparation example 8 preparation of bis (levobupivacaine) pamoic acid
3.88g of pamoic acid (10mmol) was added to 50ml of water, and 5% aqueous ammonia was added dropwise with stirring until the solid was completely dissolved to obtain an aqueous pamoic acid diamine solution (pH 8.5). 8.1g levobupivacaine hydrochloride (25mmol) are dissolved in 200ml water and heated to 60 ℃. And dropwise adding the pamoic acid diamine aqueous solution into the levobupivacaine hydrochloride aqueous solution under stirring, continuously keeping the temperature of 60 ℃ and stirring for 0.5h after the dropwise adding is finished, filtering while the solution is hot, leaching a filter cake by 50ml multiplied by 2 times, pulping and stirring the filter cake by 200ml of water, filtering, draining, and drying the filter cake at 60 ℃ overnight to obtain 9.0g of light yellow solid with the yield of 93.3%. High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) analysis confirmed that the molar ratio of levobupivacaine and pamoic acid was 2: 1.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X-ray powder diffraction pattern shows an essentially amorphous state.
Preparation example 9 preparation of bis (levobupivacaine) pamoic acid
1.95g of pamoic acid (5mmol) was suspended in 30ml of purified water, and 10% potassium hydroxide solution (6.5ml) was added to dissolve the pamoic acid solid to prepare an aqueous solution of dipotassium pamoate. 4.1g levobupivacaine hydrochloride (12.6mmol, 2.5 equivalents) are dissolved in 300ml purified water and heated to 60 ℃. And dropwise adding the prepared dipotassium pamoate water solution into the bupivacaine hydrochloride water solution under stirring, continuously stirring for 1h at 60 ℃ after dropwise adding, filtering while hot, leaching a filter cake with 50ml of purified water, pulping the filter cake with 50ml of purified water, stirring for 1h, filtering, draining, and drying the filter cake at 60 ℃ for 3-5 h to obtain 4.60g of light yellow solid with the yield of 92.0%. High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) confirmed a molar ratio of levobupivacaine to pamoic acid of 2: 1.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X powder diffractogram showed an amorphous state.
Preparation example 10 preparation of bis (levobupivacaine) pamoic acid
8g of levobupivacaine (27.7mmol, 2.7 equiv.) are suspended in 800ml of purified water, and 10% sulfuric acid (15ml) is slowly added dropwise to the suspension (pH 3-5), followed by heating to 60 ℃. Dissolving 4.5g of disodium pamoate monohydrate (10mmol) in 60ml of purified water, slowly dropwise adding the disodium pamoate aqueous solution into the existing bupivacaine hydrochloride aqueous solution under stirring at 60 ℃, continuously keeping stirring at 60 ℃ for 10 hours after dropwise adding, filtering while hot, leaching a filter cake with 100ml of purified water, pulping the filter cake with 100ml of purified water for 1 hour, filtering and draining, and drying the filter cake at 60 ℃ for 3-5 hours to obtain 9.1g of light yellow solid with the yield of 91.0%. High performance liquid chromatography (HPLC-a) and nuclear magnetic resonance (H-NMR) confirmed a molar ratio of levobupivacaine to pamoic acid of 2: 1.
Differential thermal and thermogravimetric analysis showed no endothermic peak (differential thermal analysis, SHIMADZU DTG-60A, heating rate 10 ℃/min); the results are shown as a solvate-free of bis (levobupivacaine) pamoic acid.
The X powder diffraction pattern shows an amorphous state, as shown in FIG. 1.
Preparation example 11 preparation of bis (levobupivacaine) pamoic acid
The procedure was carried out in the same manner as in production example 10 except for replacing 10% sulfuric acid with 20% aqueous citric acid (28ml) to obtain 8.7g, yield 87.0%, and the analysis result was the same as that of the compound of production example 10.
Formulation example 1
The compounds of preparation example 2 and the corresponding adjuvants are taken as shown in the following table.
Tween 801.507g and mannitol were dissolved in 150ml of water, and 26.165g of bis (levobupivacaine) pamoic acid, a compound of preparation example 2, was added under magnetic stirring to disperse. Divided into two parts, one 90.1g as 801 batch and the other 802 batch. The respective fractions were homogenized under high pressure (PandaPlus 2000) with the parameters indicated in the table. As a first suspension.
17.407g of pamoic acid (levobupivacaine) was added to the above mixture as an adjuvant, and the mixture was prepared according to the method except for inhomogeneity to give 803 batches of the first suspension.
A second solution was prepared by dissolving 6.004g of sodium carboxymethylcellulose (CMC 9M31XF PH), mannitol, 35.145g of sodium dihydrogen phosphate (dihydrate) (1.574 g) and 800ml of water with stirring, and adjusting the pH to 6.5 to 7.5 with 1mol/L sodium hydroxide.
Respectively taking about 33g of 801 and 803 batches of the first suspension, adding 200ml of the second solution, and adding water to a constant volume of 250ml to obtain a liquid medicine. The liquid medicine is filled, 10 ml/piece (corresponding to 100mg of levobupivacaine), and the liquid medicine is frozen and dried, and the procedure is as follows.
The particle size of the 801-:
| particle size μm/batch number | 801 | 802 | 803 |
| D10 | 3.61 | 2.719 | 5.309 |
| D50 | 12.895 | 10.963 | 15.463 |
| D90 | 29.163 | 24.55 | 30.413 |
The larger particle size measured may be related to flocculation of the particles in solution.
Test of Compound Properties
In the present application, the poorly soluble salts represented by formula (I) and formulations thereof according to the present invention were tested for in vitro solubility, dissolution rate, and systemic pharmacokinetics in animals.
Test example 1
Taking an excessive amount of levobupivacaine (refer to preparation example 1), placing the levobupivacaine (refer to preparation example 1) in 50mmol/L phosphate buffer solution media with pH5.5, pH6.5, pH7.4 and pH8.0, respectively, preparing 3 samples of each medium, according to a dissolution and release rate determination method (0931 second method of the four-department general rule of Chinese pharmacopoeia 2015 edition), taking 500ml of dissolution medium, the temperature of the medium is 37 ℃, the rotating speed is 50 revolutions per minute, and respectively sampling 3ml for 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 32h, 48h and 72h, centrifuging (12000rpm, 5min), and diluting 10 times by using a diluting solvent to prepare a test solution; weighing a proper amount of levobupivacaine reference substance, adding acetonitrile to dissolve, and diluting with a mobile phase to prepare a solution of about 32 mu g of levobupivacaine per 1ml to obtain the reference substance solution. Measured by HPLC-c. The results are given in the following table
| Mass concentration (μ g/ml) | pH5.5 | pH6.5 | pH7.4 | pH8.0 |
| 0.5h | 142.79 | 43.17 | 17.96 | 8.69 |
| 0.75h | 153.35 | 92.36 | 30.81 | 13.17 |
| 1h | 224.3 | 138.79 | 44.2 | 15.95 |
| 2h | 294.72 | 192.35 | 57.39 | 31.2 |
| 4h | —— | —— | 85.22 | 48.01 |
| 6h | 329.33 | 227.17 | 103.9 | 60.98 |
| 8h | 356.18 | 251.83 | 115.72 | 67.56 |
| 24h | 463.12 | 307.64 | 156.77 | 75.89 |
| 32h | 571.29 | 336.36 | 160.89 | 79.36 |
| 48h | 645.43 | 343.35 | 175.73 | 80.89 |
| 72h | 656.83 | 373.14 | 168.19 | 71.25 |
And (4) conclusion:
from the results, it can be seen that the solubility of levobupivacaine increases with decreasing pH, about 10 times the solubility at pH8.0 at pH5.5 and about 2 times the solubility at pH7.4 at pH 6.5. I.e., levobupivacaine is pH sensitive.
Test example 2
A good insoluble salt should also have stable dissolution characteristics at different pH values to adapt to changes in the body environment.
Taking a proper amount of bis (levobupivacaine) pamoic acid prepared in preparation example 2, placing the proper amount of the levobupivacaine in 50mmol/L phosphate buffer solution media with pH6.5 and pH7.4, respectively, taking 3 samples of each medium, operating according to a dissolution and release rate measuring method (0931 second method of the four-part general rule of the 2015 edition of Chinese pharmacopoeia) by taking 500ml of dissolution medium, the temperature of the medium is 37 ℃, the rotating speed is 50 revolutions per minute, respectively taking 3ml of samples in 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 24h, 32h, 48h and 72h, centrifuging (12000rpm, 5min), diluting 10 times by using a diluting solvent to be used as a sample solution; weighing appropriate amount of bis (levobupivacaine) pamoic acid, dissolving with acetonitrile, and diluting with mobile phase to obtain solution containing 16 μ g per 1ml to obtain control solution. Measured by HPLC-c.
The results are given in the following table:
and (4) conclusion:
from the results, it can be seen that the bis (levobupivacaine) pamoic acid of the present invention has a good ability to withstand different pH environments, the solubility difference between pH6.5 and pH7.4 is about 11%, and the molar ratio of the components is maintained around 2.0 for at least 72h, which can be predicted to stably maintain the drug release concentration in the pH variation of human body environment. The change range of the solubility of the levobupivacaine along with the change of the pH value is obvious, and the release concentration is predicted to be unstable under the change of the normal pH value of the organism.
Test example 3 dissolution
Taking 3 lyophilized preparations of the double (levobupivacaine) pamoic acid (preparation example 1), adding 10ml of water into each preparation for redissolving, extracting 10ml of redissolved suspension by using an injector, injecting the suspension into a dissolution cup, taking phosphate buffer solution with the pH value of 7.4 of 0.25 percent Tween 80 as dissolution medium, the temperature of the medium is 30 ℃, the volume is 900ml, measuring according to dissolution and release degree measuring method (0931 of the four-part general rule of 2015 edition in Chinese pharmacopoeia), and adopting a second method device, wherein the rotating speed is 25 r/min. Sampling 3ml at 1min, 2min, 3min, 5min and 10min respectively, filtering, collecting filtrate, and diluting with diluting solvent 10 times to obtain test solution; weighing a proper amount of a bis (levobupivacaine) pamoic acid reference substance, adding acetonitrile to dissolve and dilute the reference substance to prepare a solution containing 0.4mg per 1ml, taking the solution as a reference stock solution, precisely measuring 2ml of the stock solution, placing the solution in a 50ml measuring flask, adding 5ml of dissolution medium, and diluting the solution to a scale by using a diluting solvent to obtain a reference substance solution containing 16 mu g/ml. Measured by HPLC-c.
| % dissolution/batch number | 801 | 802 | 803 |
| 1min | 55.81 | 59.15 | 56.86 |
| 2min | 80.17 | 84.96 | 79.07 |
| 3min | 90.86 | 96.73 | 89.14 |
| 5min | 97.86 | 102.72 | 96.00 |
| 10min | 100.34 | 104.16 | 101.40 |
And (4) conclusion:
although the solubility of the bis (levobupivacaine) pamoic acid is low and the bis (levobupivacaine) pamoic acid is a poorly soluble compound, the results show that the composition of the bis (levobupivacaine) pamoic acid has a very quick dissolution speed, the 3min dissolution is more than 85%, and the dissolution characteristics of three batches have no significant difference.
Test example 4
Experiment for influence of injection dosage and particle size on pharmacokinetics of rats
12 healthy SD male rats (190-210 g, university of Anhui medical science) are selected and divided into 5 groups, 3 animals in each group are injected with levobupivacaine hydrochloride injection (Jiangsu Henrui medicine Co., Ltd.) and 801-. The groupings, dosing regimens, pharmacokinetic parameters (mean) are summarized below.
The results show that the three particle sizes of the bis (levobupivacaine) pamoic acid have no obvious difference in pharmacokinetics in vivo, and play an obvious slow release role compared with levobupivacaine hydrochloride injection; the results are that MRT, t1/2, Tmax are significantly prolonged, which is equivalent to about 2-fold or more, and Cmax is significantly reduced, which is about 50% lower. Although showing extremely rapid dissolution in vitro, long-lasting effects are also exerted in vivo. The research results show that the bis (levobupivacaine) pamoic acid has good long-acting local anesthetic effect.
The preferred embodiments of the present invention have been described in detail with reference to the accompanying drawings, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (10)
1. A complex of formula (I) or a solvate thereof:
wherein the configuration of the chiral atom is S configuration.
2. The complex or solvate thereof according to claim 1, in an amorphous state.
3. The complex or solvate thereof according to claim 1, having a median particle size D50The value is in the range of 0.1 to 50 μm.
4. A method for preparing the complex of claim 1 or a solvate thereof, comprising mixing a water-soluble levobupivacaine salt and a water-soluble pamoic acid salt in an aqueous solvent, wherein the aqueous solvent is a mixture of water and one or more of methanol, ethanol, acetone, dimethyl sulfoxide, and N, N-dimethylformamide.
5. The method of claim 4, wherein the molar ratio of levobupivacaine salt to pamoate salt is from 2:1 to 3: 1.
6. A pharmaceutical composition comprising a pharmaceutically effective amount of a complex according to any one of claims 1 to 3 or a solvate thereof and a pharmaceutically acceptable adjuvant.
7. The pharmaceutical composition of claim 6, wherein the complex or solvate thereof is of median particle size D50Solid particles having a value in the range of 0.2 to 20 μm.
8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a suspension and comprises 1 to 300mg of the complex or solvate thereof in 1ml of the suspension.
9. Use of the pharmaceutical composition according to claim 6 for the prevention or treatment of surgical, intra-operative and post-operative pain.
10. The use according to claim 9, wherein the pharmaceutical composition is administered by subcutaneous, intradermal or intramuscular injection.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATA933275A (en) * | 1973-12-17 | 1978-03-15 | Merck & Co Inc | PROCESS FOR MANUFACTURING THE NEW PILOCARPINE PAMOATE |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| WO2017167180A1 (en) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Vortioxetine pamoic acid salt and crystal form thereof |
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- 2018-09-21 CN CN201811113051.XA patent/CN110934868A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATA933275A (en) * | 1973-12-17 | 1978-03-15 | Merck & Co Inc | PROCESS FOR MANUFACTURING THE NEW PILOCARPINE PAMOATE |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| WO2017167180A1 (en) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Vortioxetine pamoic acid salt and crystal form thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄量主编, 上海科学技术出版社 * |
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