CN110483372A - The salt of Bupivacaine - Google Patents
The salt of Bupivacaine Download PDFInfo
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- CN110483372A CN110483372A CN201810455399.0A CN201810455399A CN110483372A CN 110483372 A CN110483372 A CN 110483372A CN 201810455399 A CN201810455399 A CN 201810455399A CN 110483372 A CN110483372 A CN 110483372A
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- bupivacaine
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- hydrochlorate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention is the salt of Bupivacaine, is related to the salt of 1- normal-butyl -2- (2,6- diformazan amine formyl) piperidines, especially pa not hydrochlorate, the pharmaceutical preparation comprising the salt.
Description
Technical field
The present invention relates to the officinal salts of Bupivacaine, and contain medicine of the Bupivacaine officinal salt as effective component
Object preparation.
Background technique
Bupivacaine is a kind of amides local anesthetic, entitled 1- normal-butyl -2- (2, the 6- dimethylamine formyls of chemistry
Base) piperidines, shown in structure such as following formula (I):
Its anesthesia duration is 2-3 times longer than lidocaine hydrochloride, and the spread is similar with lidocaine hydrochloride.Generally in administration 5-
Effect in 10 minutes starts, and reaches peak within 15-20 minutes.Regular injection agent (0.5%) is only capable of providing the analgesic effect less than 7h, and art
The normal sustainable 4.8-72h of pain afterwards, and be most difficult to control within this time, thus mostly using built-in catheter or infusion pump continuously give Ah
Opiates cause management inconvenient and will appear a variety of harmful adverse reactions.
2011, U.S. FDA had approved the Exparel of Pacira pharmaceutical Co. Ltd exploitation, a kind of Bupivacaine lipid
Body suspension for injection alleviates postoperative pain for controlling.Exparel is multivesicular liposome suspension, is by Bupivacaine
A kind of non-opium Bangesic combined with storage cavern foam technology.After Exparel is injected into soft tissue, Bupivacaine from
Slow release in multivesicular liposome.After Exparel single dose direct injection to operative site, it can generate and stop up to the significant of 72h
Pain acts on and can thus reduce opioid drug dosage.
The storage cavern foam technology that Exparel is used, i.e. DepoFoam are the slow controls invented by Skyepharma company, Britain
Release liposome platform patented technology.The small vesica of each of Exparel is containing Bupivacaine by many containing water chamber
And the class lipid bilayer composition of chamber is separated, and internal structure is similar to " matrix of foam-like " --- contain Bupivacaine
Aqueous compartments are constituted in the form of non-concentric, and each chamber is separated with adjacent chamber by immobilized artificial membrane, and neutral phospholipid is then
It is filled in the intersection of chamber, plays the role of rock-steady structure.Wherein the auxiliary material of its key effect is DEPC, DPPG, cholesterol
And tricaprylin.
However the pharmaceutical adjunct that Exparel is used is special, there is the risk with genotoxic potential, and pharmaceutical adjunct and work
The device is complicated for skill, preparation higher cost.In addition, the condition of storage of Exparel is more harsh, 2-8 DEG C of preservation is needed.It is above-mentioned to solve
Problem, the present invention provides a kind of Bupivacaine salt, and the preparation containing Bupivacaine salt and one or more carriers, have
Stable pharmaceutical properties not only can guarantee long-acting analgesic effect, and avoid using special auxiliary material and complicated preparation process equipment.
Summary of the invention
The present invention provides the officinal salt of Bupivacaine or its solvates, preferably are selected from pa not hydrochlorate.
In one embodiment, hydrochlorate not can be Bupivacaine pa not hydrochlorate, bis- (Bupivacaine) pas to the pa of Bupivacaine
Not hydrochlorate.
In one embodiment, hydrochlorate or its solvate, including but not limited to Bupivacaine pa be not for the pa of Bupivacaine
Hydrochlorate, Bupivacaine pa not hydrochloride hydrates, the Bupivacaine pa not solvate of the alcoholates such as hydrochlorate methanol, ethyl alcohol or ketone,
Bis- (Bupivacaine pas) not hydrochlorate, bis- (Bupivacaine) pas not hydrochloride hydrates, bis- (Bupivacaine) pas not hydrochlorate methanol, ethyl alcohol
The solvate of equal alcoholates or ketone.
The present invention also provides a kind of pharmaceutical preparation, the pharmaceutical preparation include the Bupivacaine of therapeutic dose officinal salt or
Its solvate can also contain one or more pharmaceutical carriers.The officinal salt is selected from pa not hydrochlorate.
In one embodiment, hydrochlorate not can be Bupivacaine pa not hydrochlorate, bis- (Bupivacaine) pas to the pa of Bupivacaine
Not hydrochlorate.
In one embodiment, hydrochlorate or its solvate, including but not limited to Bupivacaine pa be not for the pa of Bupivacaine
Hydrochlorate, Bupivacaine pa not hydrochloride hydrates, the Bupivacaine pa not solvate of the alcoholates such as hydrochlorate methanol, ethyl alcohol or ketone,
Bis- (Bupivacaine pas) not hydrochlorate, bis- (Bupivacaine) pas not hydrochloride hydrates, bis- (Bupivacaine) pas not hydrochlorate methanol, ethyl alcohol
The solvate of equal alcoholates or ketone.
In another embodiment, the content of active constituent is 100-2000mg.
In another embodiment, the content of active constituent is 100-798mg.
In another embodiment, the content of active constituent is 798mg.
In one embodiment, the carrier in the pharmaceutical preparation is aqueous carrier.
In one embodiment, the pharmaceutical preparation further comprises stabilizer.
In another embodiment, stabilizer is selected from low molecule alcohol, natural high molecular polymer, synthesis or semi-synthetic height
Molecularly Imprinted Polymer.
In another embodiment, stabilizer is selected from glycerol, sorbierite, gummy class, plant polyose class, cellulose family, card wave
It is general, povidone, one of glucan or polyethylene glycol or a variety of.
In a preferred embodiment, stabilizer is selected from cellulose family, Arabic gum, xanthan gum, carbopol, povidone, Portugal
One of glycan or polyethylene glycol are a variety of.
In a more preferred embodiment, stabilizer be selected from sodium carboxymethylcellulose, carboxymethyl cellulose, methylcellulose,
Hydroxypropyl cellulose, Arabic gum, xanthan gum, one of povidone or polyethylene glycol or a variety of.
In another embodiment, the content of stabilizer is 0-500mg.
In another embodiment, the content of stabilizer is 0-300mg.
In another embodiment, the content of stabilizer is 300-500mg.
In another embodiment, the content of stabilizer is 300mg.
In one embodiment, the pharmaceutical preparation further comprises wetting agent.
In another embodiment, wetting agent is selected from poly yamanashi esters, Emulsifier EL-60 class, poloxamer class, poly- dimension
Ketone, Tai Luoshamu, lecithin, sorbitan fatty acid ester class, Crodaret, bile salt or polyoxyethylene are poly-
One of oxypropylene ether block copolymers are a variety of, preferably are selected from polysorbate 20, polysorbate 40 or polyoxyethylene sorbitan monoleate
It is one or more.
In another embodiment, the content of stabilizer is 0-500mg.
In another embodiment, the content of stabilizer is 0-300mg.
In another embodiment, the content of stabilizer is 0-180mg.
In another embodiment, the content of stabilizer is 180-500mg.
In another embodiment, the content of stabilizer is 180-300mg.
In another embodiment, the content of stabilizer is 180mg.
In one embodiment, the pharmaceutical preparation further comprises osmotic pressure regulator.
In another embodiment, the osmotic pressure regulator be selected from one of mannitol, sodium chloride, sucrose, lactose or
It is a variety of；It preferably is selected from mannitol.
In another embodiment, the content of stabilizer is 0-3000mg.
In another embodiment, the content of stabilizer is 0-2400mg.
In another embodiment, the content of stabilizer is 2400-3000mg.
In another embodiment, the content of stabilizer is 2400mg.
The present invention also provides the pa of Bupivacaine not hydrochlorate or its solvate in drug of the preparation for analgesic
Using wherein the analgesic, which refers to, alleviates postoperative pain for controlling.
The present invention also provides salt described in claim 1 or its solvate comprising the therapeutic dose as active constituent
Pharmaceutical preparation with one or more pharmaceutical carriers is preparing the application in the drug for analgesic, wherein the analgesic refers to
Alleviate postoperative pain for controlling.
Term " therapeutic dose " guidance used herein causes any parameter or the improved quantity of clinical symptoms.It is actual
Dosage may change with the difference of each patient, and not necessarily refer to eliminate the total amount of all disease symptoms.
Stabilizer includes low molecule alcohol agent, natural high molecular polymer, synthesis or semi-synthetic high molecular polymer, non-
It restrictively include one of gum class, cellulose family, carbopol, povidone, glucan or polyethylene glycol or a variety of.It is optional
From in sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, Arabic gum, xanthan gum, povidone or polyethylene glycol
It is one or more.
Wetting agent expression can increase the additives that hydrophobic drug particle is readily wetted by water, including poly yamanashi esters, polyoxy second
Alkene castor-oil plant oils, poloxamer class, Tai Luoshamu, povidone, lecithin, Crodaret, bile salt or polyoxy
One of ethylene polyoxypropylene ether block copolymers are a variety of, without limitation include polysorbate 20, polysorbate 40 or
One of polyoxyethylene sorbitan monoleate is a variety of.
Bupivacaine of the invention can be purchased from business, or can prepare according to known methods.
Detailed description of the invention
The concentration time curve of Bupivacaine in rat plasma after different prescriptions is administered in attached drawing 1
Specific embodiment
The invention discloses compound officinal salt, the pharmaceutical preparation comprising officinal salt, officinal salt and its drug system
The application of agent, those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular
It is that all similar substitutions and modifications are apparent to those skilled in the art, they are considered as being included in this
Invention.Method and application of the invention is described by preferred embodiment, and related personnel can obviously not depart from this
Method described herein and application are modified or appropriate changes and combinations in summary of the invention, spirit and scope, realizing and
Using the technology of the present invention.
Below with reference to embodiment, the present invention is further explained:
The preparation of one, Bupivacaine officinal salt
1 pair of Bupivacaine pa of embodiment not hydrochlorate
Bupivacaine (28.8g, 0.1mol) is added in tri- mouthfuls of reaction flasks of 1L, ethyl alcohol (461ml), water (115ml), pa is not sour
(19.4g, 0.05mol), is stirred overnight at room temperature, and filtering, filter cake ethanol washing, 60 DEG C of dryings obtain object 42g, yield
87.1%.
1H NMR (400MHz, DMSO) δ 10.26 (s, 1H), 8.31-8.15 (m, 2H), 7.68 (d, J=7.7Hz, 1H),
7.21–6.97(m,5H),4.71(s,1H),4.11(m,1H),3.59–3.37(m,3H),3.00(s,3H),2.24(s,6H),
1.95-1.42 (m, 7H), 1.31 (dd, J=14.2,6.9Hz, 2H), 0.90 (t, J=7.4Hz, 3H)
2 Bupivacaine pa of embodiment not hydrochlorate
Under room temperature, double Bupivacaine pas not hydrochlorate (70g, 0.145mol), methylene chloride are added in 2L there-necked flask
(1400ml) stirs 48h, filtering, and filter cake is washed with methylene chloride, and 60 DEG C of dryings obtain object 44g, yield 62.8%.
1H NMR (400MHz, DMSO) δ 10.32 (s, 1H), 8.36 (s, 2H), 8.19 (d, J=7.7Hz, 2H), 7.79
(d, J=7.7Hz, 2H), 7.29 (m, 2H), 7.13 (m, 5H), 4.77 (s, 2H), 4.11 (m, 1H), 3.57 (m, 1H), 3.10
(m, 3H), 2.35 (m, 1H), 2.16 (s, 6H), 1.81-1.74 (m, 6H), 1.32 (m, 2H), 0.89 (t, J=7.4Hz, 3H)
The preparation of two, Bupivacaine salt
The preparation of 2.1 preparations
Preparation method:
1) polysorbate, carboxymethyl cellulose (CMC) and mannitol are weighed, is added to the water, 45 DEG C of dissolved clarifications take after half an hour
It is spare out.
2) API is weighed, above-mentioned solution is added, 6000 revs/min of high shear 5min use homogenizer 1000-1500bar later
Homogeneous about 30min.
2.2 prescription stability studies
2.2.1 prescription stability under the conditions of moist heat sterilization
It is taken out after sample 0100-43-A01 and 0100-43-A02 to be set to the half an hour that sterilizes in 121 DEG C of moist heat sterilization pot,
Preparation HPLC purity is measured, is shown in Table -2.The result shows that Bupivacaine suspension purity reduces, and bis- (Bupivacaine) pas are not sour
The purity of suspension is then substantially unchanged.Under the conditions of moist heat sterilization, acid supplement does not compare Bupivacaine system to bis- (Bupivacaine) pas
Agent has significant improved stability.
HPLC purity after 2 sample 0100-43-A01 and 0100-43-A02 moist heat sterilization of table
| Number | Purity (%) |
| After 0100-43-A01- sterilizing | 86.18 |
| Before 0100-43-A01- sterilizing | 99.79 |
| After 0100-43-A02- sterilizing | 98.42 |
| Before 0100-43-A02- sterilizing | 99.92 |
2.2.2 prescription stability under condition of different temperatures
After storing 1 month under the conditions of sample 0100-43-A01 and 0100-43-A02 are set 4 DEG C, measurement preparation HPLC is pure
Degree, is shown in Table 3.The result shows that Bupivacaine suspension purity reduces more, and the purity of bis- (Bupivacaine) pas not hydrochlorate suspension
It is then substantially unchanged.
3 sample 0100-43-A01 and 0100-43-A02 of table stored 1 month under the conditions of 4C after HPLC purity
| Number | Purity (%) |
| After 0100-43-A01-4C 1month | 85.66 |
| 0100-43-A01-4C is initial | 99.79 |
| After 0100-43-A02-4C 1month | 99.43 |
| 0100-43-A02-4C is initial | 99.92 |
By sample 0100-38-A01 (the not sour mono-salt suspension of Bupivacaine pa) and 0100-43-A02 (bis- (Bupivacaines)
Pa not hydrochlorate) set at room temperature with 60 DEG C under the conditions of store 37 days after, take out, measure HPLC purity, be shown in Table 4.The result shows that mono-salt
The purity reduction of suspension is more, and the reduction of the purity of half salt suspension is less.
4 sample 0100-38-A01 and 0100-43-A02 of table stored 37 days under the conditions of RT and 60C after HPLC purity
| Number | Purity (%) |
| 0100-38-A01-RT 37days | 91.15 |
| 0100-38-A01-60C 37days | 89.32 |
| API (0133-22-18)-is initial | 99.76 |
| 0100-43-A02-RT 37days | 99.29 |
| 0100-43-A02-60C 37days | 98.64 |
| 0100-43-A02- is initial | 99.92 |
Three, pharmacokinetics
9 male SD rats (weight 220-230g) are randomly divided into 3 groups, every group 3, give 7.5mg/kg dosage respectively
Bupivacaine suspension (Bup-susp, 0100-43-A01, bupivacaine concentration 11.11mg/mL), Bupivacaine pa not sour half
The Exparel (14mg/mL) of salt suspension (NORA0080-susp, 0100-43-A02,10.35mg/mL) He Yuanyan.After administration
Blood sample about 0.3mL is respectively acquired in about 10,30min, 1,2,4,8,24 (day2), 48 (day3), 72 (day4) and 96 (day5) h
Into EDTAization Eppendorf pipe, in being kept on ice to centrifugation.Blood plasma, transfer blood plasma to 96 orifice plates is collected after centrifugation in whole blood
In, it saves in -20 DEG C to LC-MS/MS and detects.By standard curve of the measurement Bupivacaine comparison medicine in blood plasma, measurement is each
The drug concentration of sample point.
Using 6.3 software of WinNonlin, calculation SD rat is asked to give NORA0080 series chemical combination respectively away from theoretical by statistics
The related pharmacokinetic parameters of each time point respective compound concentration, are detailed in table -5 after object.The conversion of rat dosage is Bu Bika
Because being 7.5mg/kg.
5 rat of table gives the pharmacokinetic parameter of Bupivacaine in blood plasma after different prescriptions
The result shows that under the conditions of same dose, Bupivacaine salt pref prepared by the present invention, after rat is administered, tool
There is Sustained drug releasing effect similar with Exparel；And plasma exposure amount is only the 17% of Exparel, substantially compared with Exparel
It reduces, is expected to reduce the system toxicity of drug.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of art technology
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (15)
1. the pa of Bupivacaine not hydrochlorate or its solvate.
2. a kind of pharmaceutical preparation, comprising salt described in claim 1 or its solvate as active constituent and a kind of or more
Kind pharmaceutical carrier.
3. pharmaceutical preparation according to claim 2, wherein carrier is aqueous carrier.
4. pharmaceutical preparation according to claim 2 further comprises stabilizer.
5. pharmaceutical preparation according to claim 4, wherein stabilizer is selected from low molecule alcohol, natural high molecular polymerization
Object, synthesis or semi-synthetic high molecular polymer.
6. pharmaceutical preparation according to claim 4, wherein stabilizer is selected from glycerol, sorbierite, gummy class, plant polyose
Class, cellulose family, carbopol, povidone, one of glucan or polyethylene glycol or a variety of；It preferably is selected from cellulose family, I
Primary glue, xanthan gum, carbopol, povidone, one of glucan or polyethylene glycol or a variety of；More preferably from carboxymethyl cellulose
In sodium, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, Arabic gum, xanthan gum, povidone or polyethylene glycol
It is one or more.
7. pharmaceutical preparation according to claim 2 further comprises wetting agent.
8. pharmaceutical preparation according to claim 7, wherein wetting agent be selected from poly yamanashi esters, Emulsifier EL-60 class,
Poloxamer class, povidone, Tai Luoshamu, lecithin, sorbitan fatty acid ester class, Crodaret, gallbladder
One of juice salt or polyoxyethylene poly-oxygen propylene aether block copolymer are a variety of, preferably are selected from polysorbate 20, polysorbate 40
Or one of polyoxyethylene sorbitan monoleate or a variety of.
9. pharmaceutical preparation according to claim 2 further comprises osmotic pressure regulator.
10. the pharmaceutical preparation according to shown in claim 9, wherein osmotic pressure regulator is selected from mannitol, sodium chloride, sucrose, cream
One of sugar is a variety of；It preferably is selected from mannitol.
11. pharmaceutical preparation according to claim 2, wherein active constituent is selected from Bupivacaine pa not hydrochlorate, Bupivacaine
Pa not hydrochloride hydrates, the Bupivacaine pa not solvate of the alcoholates such as hydrochlorate methanol, ethyl alcohol or ketone, bis- (Bupivacaine) pas
Not hydrochlorate, bis- (Bupivacaine) pas not hydrochloride hydrates, bis- (Bupivacaine) pas not alcoholates such as hydrochlorate methanol, ethyl alcohol or ketone
Solvate.
12. salt according to claim 1 or solvate, the salt is selected from Bupivacaine pa not hydrochlorate, bis- (Bupivacaines
Pa) not hydrochlorate.
13. application of the salt described in claim 1 in drug of the preparation for analgesic.
14. application of the pharmaceutical preparation described in claim 2-12 in drug of the preparation for analgesic.
15. the analgesic as described in claim 13 or 14 includes alleviating postoperative pain for controlling.
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Application publication date: 20191122 |