CN108143733B - Anesthetic analgesic pharmaceutical composition and preparation method thereof - Google Patents
Anesthetic analgesic pharmaceutical composition and preparation method thereof Download PDFInfo
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- 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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
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- 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
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention relates to an anesthetic analgesic pharmaceutical composition, which comprises a compound pharmaceutical composition containing remazolen and derivatives thereof and anesthetic analgesics, wherein the compound pharmaceutical composition can be used as a sedative hypnotic.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound pharmaceutical composition containing remazolen and derivatives thereof (compounds shown in formula I) and an anesthetic analgesic agent and can be used as a sedative-hypnotic agent, and particularly relates to a freeze-dried powder injection preparation containing remazolen and derivatives thereof and the anesthetic analgesic agent.
Background
A compound of formula (I) benzodiazepine
The following were used:
r is H, CH3Ethyl, isopropyl.
The compound of the formula (I) is a novel benzodiazepine compound, belonging to a short-acting sedative. The medicine can be clinically used for program sedation, general anesthesia induction and maintenance, ICU patient tranquilization and the like. Short-acting sedatives can rapidly restore consciousness and allow patients to be discharged as quickly as possible. The demand of the medicines is particularly urgent in the face of the current situation that the short-term hospitalization cases are gradually increased. At present, midazolam is the dominant drug in the domestic sedative-hypnotic market, and research data shows that compared with the similar drug midazolam, the formula (I) has the advantages of quicker response, shorter sedative effect duration and no excessive inhibitory action on respiratory and cardiovascular systems, so the formula (I) has obvious advantages in short-time diagnosis and surgical application. In addition, the formula (I) is rapid in metabolism, independent of cellular P450 enzyme metabolism, capable of being metabolized by various organs, low in metabolite activity, capable of reducing interaction among medicines and capable of being used by patients with damaged metabolic organ functions.
It is reported in CN101501019B that the base of the compound of formula (I) wherein R is methyl is stable when stored at 5 ℃, but deliquescence of the sample stored at 40 ℃/75% relative humidity (open) is observed, the color changes to yellow to orange, and a significant content reduction is shown relative to the initial content. Researchers have therefore synthesized the benzenesulfonate salt of (I) in the hope of improving its chemical stability for use in the preparation of pharmaceuticals.
EP2089378B1 reports crystalline forms of the ethanesulfonate of the compound of formula (I), wherein R is methyl, and methods for the preparation thereof. CN102964349A reports a crystal form of tosylate of a compound represented by formula (I) (R is methyl) and a preparation method thereof.
CN103202815B reports a method for preparing a lyophilized formulation of a salt of a compound of formula (I) (R is methyl), which describes the use of mannitol or glycine as excipient. TW201400119A reported that the formula of the compound of formula (I) (R is methyl) with mannitol, glycine was unstable and that the compound of formula (I) showed strong degradation in a short time, producing the following impurity A,
r is H, CH3Ethyl, isopropyl.
The opioid medicines such as fentanyl, remifentanil, sufentanil and the like are a new synthesized opioid mu receptor agonist, have the characteristics of quick response, short action time, easy elimination, no accumulation, independence on liver and kidney functions, quick reviving, strong controllability and the like, are favorable for keeping the stability of cardiovascular functions of patients in operation, and have blocking effect on pain caused by operation and reflex arcs generated by excitation of sympathetic nerves and conducted to nerve centers.
Clinically, the compound shown as the formula (I) is used as a short-acting sedative for procedural sedation, general anesthesia induction and maintenance, ICU patient tranquilization and the like, but the patient is easy to have symptoms of morning insomnia, daytime anxiety and the like after being taken; high-dose remazolin (the compound shown in the formula (I) (R is methyl)) can cause adverse reactions such as absorption inhibition, drug accumulation and the like, and has obvious hypotension and extrapyramidal symptoms.
Disclosure of Invention
Through a large number of researches, the inventor discovers that the compound shown in the formula (I) and opioid medicines such as fentanyl, remifentanil, sufentanil, carfentanil, morphine, nalbuphine, hydromorphone, oxycodone, ropivacaine and the like are prepared into a compound composition preparation, so that adverse reactions caused by the compound shown in the formula (I) can be effectively overcome; meanwhile, the onset time of the narcotic analgesic can be shortened, the narcotic analgesic effect of the opioid can be enhanced and prolonged, the uncomfortable feelings and adverse reactions of injection pain, respiratory depression, constipation, nausea, vomiting and the like of a patient can be effectively reduced, and the medication compliance of the patient can be obviously improved.
The compound composition can effectively eliminate pain of a patient in the operation process, fear and mental stress caused by viscera traction, thereby protecting the physical and mental health of the patient, being beneficial to the smooth implementation of the operation and improving the operation satisfaction of the patient.
When the compound composition is used for preparing a freeze-dried powder preparation, the opioid can be obviously found to inhibit the generation of impurity A in the process of preparing the compound composition shown in the formula (I), and the compound shown in the formula (I) also improves the stability of the opioid.
Accordingly, it is an object of the present invention to provide a short-acting benzodiazepine for injection
A salt pharmaceutical composition which can effectively overcome the adverse reactions of the compound shown in the formula (I), enhance the narcotic analgesic effect of opioid drugs, and effectively eliminate the pain of patients during the operation, fear and mental stress caused by viscera traction.
The invention also aims to provide a preparation method of the composition, and the screening of the freeze-drying protective agent is firstly tried, the appearance and the dissolution time limit of the product are taken as the investigation indexes, the commonly used freeze-drying protective agent is screened, and the results are as follows:
from the test results, the product added with sucrose, sodium chloride, glucose, povidone and D (+) -trehalose has poor appearance quality, loose atrophy, long dissolution time, high water content and is not beneficial to the stability of the product, so the product is not easy to be selected as a freeze-drying protective agent; the skeleton using dextran, mannitol, glycine and lactose as matrix is firm, not easy to break by vibration, full in appearance, smooth and fine in skeleton surface, good in dissolution, low in water content of product, beneficial to product stability, and can be selected as the freeze-drying protective agent of the compound.
Therefore, the composition adopts dextran, mannitol, glycine and lactose as freeze-drying protective agents, the stability of the product is obviously improved, the generation of impurity A in the compound preparation shown in the formula (I) is effectively inhibited, and the stability of an active component opioid analgesic is enhanced due to the lower water content. The preparation method provided by the invention has the advantages of short process period, less auxiliary material consumption, low process cost and satisfactory effect, and only needs 1-2 days.
An anesthetic analgesic pharmaceutical composition for injection and a preparation method thereof, the composition contains a salt of formula (I), an anesthetic analgesic, a freeze-drying protective agent and a pH regulator. The salt of the compound of formula (I) and the opioid analgesic is an aromatic sulfate salt, a sulfonate salt, a methanesulfonate salt, a hydrochloride salt, a hydrobromide salt, an acetate salt, a propionate salt, a sulfate salt, a phosphate salt, a lactate salt, a succinate salt, a maleate salt, a fumarate salt, a tartrate salt, a citrate salt, a malate salt, a citrate salt and any combination thereof; preferably hydrochloride, citrate, sulfate, benzene sulfonate, toluene sulfonate, ethane sulfonate, and methane sulfonate.
The compound is prepared by dissolving the compound in water for injection to prepare liquid medicine and freeze-drying the liquid medicine, wherein the liquid medicine comprises the following components in percentage by mass and volume:
the freeze-drying protective agent is at least one or the combination of dextran, mannitol, glycine and lactose; the pH regulator is hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, etc.
Further, the compound is prepared by dissolving the compound in water for injection to prepare a liquid medicine and then freeze-drying the liquid medicine, wherein the liquid medicine comprises the following components in percentage by mass and volume:
the freeze-drying protective agent is at least one or the combination of dextran, mannitol, glycine and lactose; the pH regulator is hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, etc.
The invention also provides a preparation method of the narcotic analgesic pharmaceutical composition, which comprises the following steps: according to the feeding ratio, putting the freeze-drying protective agent into water for injection to be dissolved, adjusting the pH value of the solution to 2.5-4.5 by using a pH regulator, adding the salt of the compound shown in the formula (I) and the salt of the narcotic analgesic agent while stirring, stirring until the salts are completely dissolved, fixing the volume, filtering, and freeze-drying to obtain a finished product; the mass volume ratio content of the compound shown in the formula (I) in the liquid medicine, the anesthetic analgesic and the freeze-drying protective agent is respectively as follows:
before the filtration process, in order to further improve the quality of the preparation and reduce the content of impurities in the medicine, medicinal active carbon is added according to the weight-volume ratio of 0.01-0.2% before the filtration, after stirring and adsorbing for 10-50 minutes, a 0.45 mu m filter membrane is decarburized and filtered, and then a 0.22 mu m filter membrane is used for degerming and filtering.
The freeze drying process is as follows:
(1) a pre-freezing section: and filtering the filled solution, putting the solution into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, and keeping the temperature of the product at-30 to-45 ℃ for 1 to 5 hours.
(2) A sublimation drying stage: vacuumizing to maintain the vacuum of the front box between 10 and 50pa, and slowly increasing the oil temperature to ensure that the product temperature is not higher than 15 ℃ before sublimation drying is finished.
(3) And (3) analysis and drying stage: heating the product to maintain the temperature at 20-25 ℃ for 5-18 h.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
The composition was also studied for aerosol and inhalation.
The aerosol has the advantages of small dose, uniform distribution, quick effect, good effect, convenient use and the like, can reduce the side effect of gastrointestinal tracts when being inhaled, avoids the irritation to wound surfaces when being externally used, can determine the control dose of a valve, and has quick and positioning effects, so that preliminary preparation and research are carried out on the aerosol of the composition.
The components of the compound are a compound shown in a formula (I) and an opioid narcotic analgesic, wherein a surfactant is lecithin, a dispersing agent is absolute ethyl alcohol, and a propellant is tetrafluoroethane.
The preparation process mainly comprises the following steps: crushing a compound shown as a formula (I) and an opioid narcotic analgesic to be less than 5-7 mu m; respectively weighing 20-50 g of the compound shown in the formula (I), 0.1-5 g of opioid narcotic analgesic, 4.6-5 g of lecithin and 1kg of absolute ethyl alcohol according to a certain proportion; ③ firstly taking 2/3 absolute ethyl alcohol, adding lecithin, homogenizing and stirring for 20min under a high-shear homogenizer; adding the compound shown in the formula (I) and the opioid narcotic analgesic into the upper liquid, and stirring for 30min under a high-shear homogenizer; supplementing the rest anhydrous ethanol to full volume, stirring for 20min, and circulating for 15 min; filling a bundle valve, filling a propellant tetrafluoroethane, detecting leakage and weighing; sixthly, installing an actuator (cover).
Through preliminary study on the aerosol, the preparation has the advantages of quicker response speed, more lasting anesthesia, analgesia and sedation effects, no moisture, less impurities generated by product degradation, more stable product and safer medication, and the compliance of the medication crowd is increased because of no wound to a human body.
Drawings
FIG. 1 shows that the compound of formula (I) in combination with remifentanil and nalbuphine slows down the respiratory rate inhibition by remifentanil and nalbuphine
FIG. 2 improvement in exhalation duration for the group of compounds of formula (I) in combination with remifentanil and nalbuphine
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the invention are given solely for the purpose of illustration and not as a limitation of the invention, and therefore, simple modifications of the invention in the process precursors of the invention are within the scope of the claimed invention.
Example 1: composition for preparing narcotic analgesic
Prescription:
the preparation method comprises the following steps: according to the feed ratio, dextran and glycine are put into about 90 percent of injection water according to the formula amount for dissolving, and the pH value of the solution is adjusted to 2.5-3.7 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and remifentanil hydrochloride while stirring, stirring until the benzene sulfonate and the remifentanil hydrochloride are completely dissolved, measuring the pH value of the solution to be 2.5-3.7, and then using water for injection to fix the volume to the full amount of the prescription. 0.1% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 30 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 3 hours.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 30Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 5 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 20 ℃ for 10 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 2: composition for preparing narcotic analgesic
Prescription:
the preparation method comprises the following steps: according to the feed ratio, lactose is put into about 90 percent of injection water according to the formula amount for dissolving, and the pH value of the solution is adjusted to 3.5-4.8 by a pH regulator. Then adding the benzene sulfonate of the formula (I) and fentanyl citrate while stirring, stirring until the benzene sulfonate and the fentanyl citrate are completely dissolved, measuring the pH value of the solution to be 3.5-4.8, and then using water for injection to fix the volume to the full amount of the prescription. 0.01% (w/v) of medicinal charcoal was added by volume to the solution, and stirred for 40 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 5 hours.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 10Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is reduced by 0 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 20 ℃ for 5 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 3: composition for preparing narcotic analgesic
Prescription:
| components | Dosage of |
| Benzenesulfonate of compound represented by formula (I) (R is methyl in terms of base) | 35g |
| Sufentanil citrate (in terms of base) | 1.2g |
| Dextran | 7g |
| Mannitol | 85g |
| pH regulator | Proper amount of |
| Water for injection | The volume is up to 1000ml |
The preparation method comprises the following steps: according to the feed ratio, dextran and mannitol are put into about 90% of injection water according to the formula amount to be dissolved, and the pH value of the solution is adjusted to 3.8-4.5 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and sufentanil citrate while stirring, stirring until the benzene sulfonate and the sufentanil citrate are completely dissolved, measuring the pH value of the solution to be 3.8-4.5, and then using water for injection to fix the volume to the full amount of the prescription. 0.05% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 50 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 1 hour.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 20Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 10 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 25 ℃ for 5 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 4: composition for preparing narcotic analgesic
Prescription:
| components | Dosage of |
| Benzenesulfonate of a compound represented by the formula (I) (R is hydrogen in terms of a base) | 47g |
| Morphine hydrochloride (in base) | 4.6g |
| Glycine | 80g |
| pH regulator | Proper amount of |
| Water for injection | The volume is up to 1000ml |
The preparation method comprises the following steps: according to the feed ratio, glycine is put into about 90 percent of injection water according to the formula amount to be dissolved, and the pH value of the solution is adjusted to 5.5-6.5 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and morphine hydrochloride while stirring, stirring until the benzene sulfonate and the morphine hydrochloride are completely dissolved, measuring the pH value of the solution to be 5.5-6.5, and then using water for injection to fix the volume to the full amount of the prescription. 0.2% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 10 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 1 hour.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 40Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 15 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 18 ℃ for 18 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 5: composition for preparing narcotic analgesic
Prescription:
the preparation method comprises the following steps: according to the feed ratio, dextran and glycine are put into about 90 percent of injection water according to the formula amount for dissolving, and the pH value of the solution is adjusted to 4.2-5.5 by using a pH regulator. Then adding benzene sulfonate of formula (I) and oxycodone hydrochloride while stirring, stirring until the benzene sulfonate and the oxycodone hydrochloride are completely dissolved, measuring the pH value of the solution to be 4.2-5.5, and then adding water for injection to fix the volume to the full amount of the prescription. 0.1% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 30 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 1 hour.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 50Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 15 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 8 ℃ for 15 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 6: composition for preparing narcotic analgesic
Prescription:
| components | Dosage of |
| Benzenesulfonate of compound represented by formula (I) (R is ethyl in terms of base) | 70g |
| Hydromorphone hydrochloride (in bases) | 6g |
| Dextran | 150g |
| pH regulator | Proper amount of |
| Water for injection | The volume is up to 1000ml |
The preparation method comprises the following steps: according to the feed ratio, dextran is put into about 90 percent of injection water according to the formula amount to be dissolved, and the pH value of the solution is adjusted to 2.8-3.6 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and hydromorphone hydrochloride while stirring, stirring until the benzene sulfonate and the hydromorphone hydrochloride are completely dissolved, measuring the pH value of the solution to be 2.8-3.6, and then using the injection water to fix the volume to the full volume of the prescription. 0.15% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 45 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 1 hour.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 45Pa for maintenance, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 7 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 16 ℃ for 8 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 7: composition for preparing narcotic analgesic
Prescription:
| components | Dosage of |
| Formula (A), (B) andI) benzenesulfonate (R is methyl, in terms of base) | 58g |
| Nalbuphine hydrochloride (in base) | 5g |
| Glycine | 145g |
| pH regulator | Proper amount of |
| Water for injection | The volume is up to 1000ml |
The preparation method comprises the following steps: according to the feed ratio, glycine is put into about 90 percent of injection water according to the formula amount to be dissolved, and the pH value of the solution is adjusted to 3.5-4.7 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and nalbuphine hydrochloride while stirring, stirring until the benzene sulfonate and the nalbuphine hydrochloride are completely dissolved, measuring the pH value of the solution to be 3.5-4.7, and then adding water for injection to fix the volume to the full volume of the prescription. 0.12% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 36 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 2 hours.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 15Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 12 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 8 ℃ for 16 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 8: composition for preparing narcotic analgesic
Prescription:
the preparation method comprises the following steps: according to the feed ratio, mannitol and glycine are put into about 90% of injection water according to the formula amount to be dissolved, and the pH value of the solution is adjusted to 2.5-3.7 by using a pH regulator. Then adding the benzene sulfonate of the formula (I) and alfentanil hydrochloride while stirring, stirring until the benzene sulfonate and the alfentanil hydrochloride are completely dissolved, measuring the pH value of the solution to be 2.5-3.7, and then using water for injection to fix the volume to the full amount of the prescription. 0.08% (w/v) of medicinal charcoal was added by volume of the solution and stirred for 30 minutes. The liquid medicine is firstly filtered by a 0.45 mu m microporous filter membrane and then filtered by a 0.22 mu m microporous filter membrane.
And (3) freeze-drying process:
(1) a pre-freezing stage: filling the filtered liquid, putting the liquid into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, reducing the temperature of the product to-30-35 ℃, and maintaining for 3 hours.
(2) A sublimation drying stage: vacuumizing, reducing the vacuum of the front box to 15Pa for maintaining, slowly increasing the oil temperature, and ensuring that the temperature of the product is lower than 12 ℃ before the sublimation drying of the sample is finished.
(3) And (3) analysis and drying stage: the oil temperature was slowly increased and the samples were maintained above 20 ℃ for 15 hours.
(4) And after the freeze-drying process is finished, shutting down the machine, pressing the stopper, taking out the cabinet and rolling the cover.
Example 9: preparation of Aerosol
Prescription:
| components | Dosage of |
| Benzenesulfonate of compound represented by formula (I) (R is methyl in terms of base) | 50g |
| Remifentanil hydrochloride (in terms of base) | 0.5g |
| Lecithin | 4.6g |
| Anhydrous ethanol | 1kg |
The preparation method comprises the following steps:
crushing a compound shown as a formula (I) and remifentanil hydrochloride to be less than 5-7 mu m; respectively weighing 50g of the compound shown in the formula (I), 0.5g of remifentanil hydrochloride, 4.6g of lecithin and 1kg of absolute ethyl alcohol according to a certain proportion; ③ firstly taking 2/3 absolute ethyl alcohol, adding lecithin, homogenizing and stirring for 20min under a high-shear homogenizer; adding the compound shown in the formula (I) and the opioid narcotic analgesic into the upper liquid, and stirring for 30min under a high-shear homogenizer; supplementing the rest anhydrous ethanol to full volume, stirring for 20min, and circulating for 15 min; filling a bundle valve, filling a propellant tetrafluoroethane, detecting leakage and weighing; sixthly, installing an actuator (cover).
Example 10: toxicity testing of Aerosol formulations
1. 36 clean-grade healthy SD female rats with body mass (192 +/-6) g of experimental animals are used for chronic toxicological experiments; 30 clean-grade healthy Kunming female white mice with body mass (23 +/-2) g are used for acute toxicological experiments. Feeding with common feed and drinking water. The room temperature is controlled at 24 +/-4 ℃, the humidity is controlled at 51 +/-6 percent, and natural illumination is carried out.
2. According to the acute toxicity experiment (Chinese medicine and natural medicine research and registration working manual), 30 clean-grade healthy Kunming female mice are selected and randomly divided into 2 groups, and 15 mice are respectively selected from a treatment group and a blank control group. The treatment group was administered 2 times daily with the aerosol of example 9, in a dose converted from normal adult inhalation to mice. The blank control group was administered with 1mL/20g of 0.9% sodium chloride injection.
3. Chronic toxicity test clean grade healthy SD female rats 36 were randomly divided into 4 groups, a normal control group and small, medium and large dose groups of the treatment group, 9 each. The control group is intragastrically administered with 1ml/20g of sodium chloride injection with 0.9% of body mass, the small, medium and large dosage groups of the treatment group are 20, 30 and 40 times of the normal dosage of adults converted into rat dosage, and the intragastrically administered for 2 times a day with an experimental period of 3 months.
4. Acute toxicity test results the mice do not die within 10 days after administration, and the mice observed after administration have normal appearance, hair color and luster, normal social behaviors and reactions, and normal ingestion and excretion. After 10 days, the dissected body was manually sacrificed and observed to see that no abnormality occurred in the heart, liver, spleen, lung, kidney, brain, ovary, and uterus. And (3) pathological examination: hematoxylin-eosin (HE) staining, smooth surface of viscera, orderly arrangement of tissue structure, normal cell size and shape, clear staining of cytoplasm and nucleus, and no statistical significance (P > 0.05) compared with blank control group.
5. Results of chronic toxicology experiments the appearance, hair color, social behavior, irritation and the like of rats in small, medium and large dose groups and normal control groups of rats in the treatment group and the comparison and difference of interest in the surrounding environment, food and water have no statistical significance (P is more than 0.05). The body mass of the 4 groups of rats after the experiment is increased compared with that of the rats before the experiment (P is less than 0.05), but the comparison difference of the body mass of the 4 groups of rats after the experiment has no statistical significance (P is more than 0.05), and the comparison difference of the hematocytology index, the hematology index and the important organ coefficient of the 4 groups of rats after the experiment has no statistical significance (P is more than 0.05). After 4 groups of rats are sacrificed, the vital organs are examined by pathological section staining and HE staining. The treated rats have orderly organ tissue structure arrangement, normal cell size and form, clear cytoplasm and nucleus staining, and no statistical significance (P is more than 0.05) compared with the normal control group.
Toxicity tests show that after the aerosol is administrated, no toxic reaction is caused after mice and rats.
Comparative example 1
The preparation of this formulation is carried out with reference to page 18 of the specification of patent CN201380036582.2,
lactose was dissolved in about 50ml of water. The benzene sulfonate salt of remimazolam was added and stirred until dissolved. Once dissolved, the pH of the solution was adjusted to 3.10 ± 0.05 with 0.5M hydrochloric acid/2M sodium hydroxide. A placebo solution and a solution containing only the benzene sulfonate salt of remimazolam were prepared in the same manner. Each solution was made up to 100ml and 1.2ml of each solution was aliquoted into 2ml vials. The formulation was lyophilized using a Virtis Genesis 25EL freeze dryer according to the following cycle:
freezing step
Drying step
| Step (ii) of | Temperature (. degree.C.) | Time (min) | Pressure (mTorr) |
| 1 | -45 | 10 | 100 |
| 2 | -25 | 200 | 100 |
| 3 | -25 | 3640 | 100 |
| 4 | -30 | 275 | 70 |
| 5 | 30 | 1300 | 70 |
After freeze-drying, the samples were stored at 2-8 ℃ respectively.
Example 11 stability investigation test
The products of examples 1 to 8 and comparative example 1 were subjected to the influence factor test, and were allowed to stand at a high temperature of 60 ℃ for 10 days under the conditions of 4500lx ± 500lx, respectively, and sampled once every 5 days and 10 days, respectively, to examine the indices shown in the following table:
the HPLC detection conditions were as follows:
column: YMC ODS-AQ,250X 4.6mm,3 μm particle size
Mobile phase: a: 0.01% trifluoroacetic acid in water
B: 0.01% trifluoroacetic acid in acetonitrile
Gradient:
| time (min) | A | B％ | |
| 0 | 75 | 25 | |
| 20.0 | 60 | 40 | |
| 30.0 | 20 | 80 | |
| 32.5 | 75 | 25 | |
| 40 | 75 | 25 |
Flow rate: 1.0ml/min
Column temperature: 40 deg.C
And (3) detection: UV of 230nm
Injection volume: 10 μ l
TABLE 1 product influence factor test results
The products of examples 1 to 8 and comparative example 1 were packaged on the market and stored for 6 months at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5%, and the results were shown in the following table:
table 2 stability test results of the products
The above mentioned influencing factors and accelerated tests show that the product prepared by the invention has stable quality and less impurities compared with the comparative test 1. The treatment effect of the product is effectively improved, the side effect is reduced, the cost is reduced, and better benefit is created.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
Example 12 irritation test examination
Examples preparation of test solutions: the samples of example 1, example 2, example 3 and example 7 were prepared into 20.0mg/ml solutions (based on the base of the drug) by 0.9% sodium chloride injection, respectively, and prepared for use.
Preparation of a comparative test solution: a sample of the comparative formulation was prepared according to comparative example 1, and the comparative formulation was prepared as a 20.0mg/ml solution (based on the base of the compound represented by formula (I)) using 0.9% sodium chloride injection and prepared for use.
Test animals: new Zealand white rabbits, female, weight 2.2 ~ 2.8 kg;
the test method comprises the following steps: 20 New Zealand white rabbits were randomly divided into 5 groups, a positive control group and a test group. The positive control group was given the control test solution, and the test groups were given the example test solutions, respectively. Each group was intravenously injected at 3.2mg/Kg (8.0mg/ml) into the left ear margin of rabbits, and the right side was separately injected with an equal amount of physiological saline as a control. The injection time is 3min, 1 time per day, and the dosage is continuously 7 days, and the injection part and surrounding tissues are visually observed before each dosage and 48, 72 and 96 hours after the last dosage for whether the irritation phenomenon such as red swelling and congestion exists or not and then are scored. The animals were sacrificed 96h after the last administration, the injection sites were clipped to the blood vessels and surrounding tissues of the cardiac end, washed with physiological saline, fixed with formaldehyde, dehydrated conventionally, embedded in paraffin, sectioned, stained, and examined pathohistologically with light microscopy.
And (4) counting results: the abnormal phenomena of congestion, edema and the like can be observed after the physiological saline is injected into the right ear of each white rabbit intravenously before and after each administration; the peripheral vein injection part of the left ear of the positive control group is near the peripheral blood vessel of the heart and has mild hyperemia and edema; the vein injection part at the outer edge of the left ear of the test group has no vein abnormal phenomenon. Rabbit ear vein tissue sections were observed and scored. No obvious edema and inflammatory cell infiltration were observed around the marginal vein of the ear injected with physiological saline. The marginal veins of the ear of the positive control group are slightly dilated and congested, the surrounding of the blood vessels is loose and connective tissue edema with inflammatory cell infiltration, and the surrounding of the blood vessels of the test group has no obvious edema and inflammatory cell infiltration. The test results are shown in tables 1 and 2 below.
TABLE 3 evaluation results of rabbit vascular irritation symptom observation
Note: <0.5 no irritation; <2.5 mild irritation; <4.5 moderate stimulation; >4.5 Severe stimulation
TABLE 4 evaluation results of rabbit vascular-irritant histopathology examination
Note: <0.5 no irritation; <2.5 mild irritation; <4.5 moderate stimulation; >4.5 Severe stimulation
The results show that the test group has no stimulation by naked eye observation in 7 days of continuous administration, 48 hours, 72 hours and 96 hours before each administration and after the last administration; the pathological tissue section examination result shows that other abnormalities are not seen in the test group, and the pathological tissue section examination result has no obvious difference compared with the physiological saline side. The positive control group had mild hyperemia and edema after administration. Therefore, the medicinal composition has no irritation to blood vessels and is superior to a comparative preparation.
Example 13 hemolysis and coagulation test
The safety of the pharmaceutical composition prepared by the invention is verified by hemolytic and aggregation tests.
Examples preparation of test solutions: the samples of example 1, example 2, example 3 and example 7 were dissolved in 0.9% sodium chloride solution using 0.9% sodium chloride injection to prepare 20.0mg/ml (based on the drug base) solution as a test solution for use.
Preparation of a comparative test solution: a sample of the comparative preparation was prepared according to comparative example 1, and the comparative preparation was prepared as a solution of 20mg/ml (based on the base of the compound represented by formula (I)) using a 0.9% sodium chloride injection as a positive control solution for future use.
Preparation of 2% erythrocyte suspension: the blood of healthy rabbit is taken and put into a conical flask, and the glass rod is used for stirring the blood to remove fibrinogen, so that defibrinated blood is formed. Adding about 10 times of 0.9% sodium chloride solution, shaking, centrifuging for 15 minutes at 1000-1500 rpm, removing supernatant, and washing the precipitated red blood cells with 0.9% sodium chloride solution for 2-3 times until the supernatant is not red. The red blood cells were made up to 2% suspension in 0.9% sodium chloride solution for testing.
14 clean glass test tubes are taken and numbered, wherein tubes No. 1 and 2 are sample test tubes of example 1, tubes No. 3 and 4 are sample test tubes of example 2, tubes No. 5 and 6 are sample test tubes of example 3, tubes No. 7 and 8 are sample test tubes of example 7, tubes No. 9 are negative control tubes, tubes No. 10 are positive control tubes, tubes No. 11 are sample test tube of example 1, tubes No. 12 are sample test tube of example 2, tubes No. 13 are sample test tube of example 3, and tubes No. 14 are sample test tube of example 7. The following table shows that the red blood cell suspension 2%, the sodium chloride solution 0.9% and the distilled water are added in turn, mixed uniformly, and then immediately placed in a thermostat with the temperature of 37 +/-0.5 ℃ for incubation, and after 3 hours, hemolysis and coagulation reaction are observed.
TABLE 5 hemolysis and coagulation test protocol
The hemolysis condition of each tube is observed by naked eyes, and the result shows that the hemolysis phenomenon appears within 15 minutes after the positive control tube (tube No. 10) is added with distilled water; no. 11-14 tubes are colorless clear liquid, the erythrocytes of No. 1-9 tubes sink, and the supernatant is colorless clear and almost has no difference from the erythrocytes of No. 11-14 tubes, which shows that the samples of examples 1, 2, 3 and 7 of the invention have no hemolysis phenomenon; the tube No. 1-9 was gently inverted 3 times, and it was found that the red blood cells were uniformly dispersed, indicating that there was no aggregation of red blood cells. The results show that: the samples prepared in examples 1, 2, 3 and 7 of the present invention were not hemolyzed and aggregated with rabbit erythrocytes.
The above tests were also performed on lyophilized formulations prepared in other examples of the present invention, and similar results were obtained.
Example 14 allergy test
Healthy guinea pigs were taken and divided into three groups of 6 animals by weight. The sample group (prepared in example 1 of the present invention), the ovalbumin positive control group and the 0.9% sodium chloride injection negative control group were injected, respectively. The systemic anaphylaxis scoring criteria and test results are shown in the following table.
TABLE 6 Total allergy Scoring criteria
TABLE 7 test results
The result shows that the sample of the invention has no sensitization effect and no allergy to the tested animal.
The above tests were also performed on the lyophilized powder formulations and aerosols prepared in other examples 2 to 9 of the present invention, and similar results were obtained.
Example 15 clinical trial
1. Clinical data
1.1 inclusion criteria: patients with clinically confirmed Osteoarthritis (OA), osteoporosis, soft tissue injury, cervical spondylosis, lumbar intervertebral disc protrusion and the like; ② 23-65 years old, male and female; and thirdly, the person willing to be tested and signed with an informed consent.
1.2 exclusion criteria: patients who are treated with analgesic in 4 hours or oral slow-release analgesic in 12 hours before the test, use monoamine oxidase (MAO) inhibitor in 2 weeks and have received immunosuppressant, chloroquine and adrenocortical hormone for 3 weeks; (xii) smokers and alcohol addicts, respiratory depression, and respiratory obstruction; taking other drug tests or using drugs which are harmful to the viscera within 1-3 months; fourthly, the patients with serious damage to the functions of heart, liver and kidney and the hematopoietic system or the patients with other serious diseases; any one of the components in the observation is the same or similar to the drug allergy history; sixthly, women in pregnancy and lactation and women in rest childbearing age in the near term are planned; seventhly, suffering from nervous organic diseases and mental abnormality, and unable to cooperate with the disease.
1.3 case status: 264 patients are all inpatients or outpatients, simple random (1:1) single-blind control tests are adopted, SAS software and an envelope card method are randomly adopted, and the selected patients are divided into a treatment group (132) and a control group (132) according to the treatment sequence. Wherein, the treatment groups comprise 83 men and 49 women, the age is 54.3 +/-7 years, the weight is 73.6 +/-10 kg, the VAS score is 5.1276 +/-1.3187, and the disease course is 3.1 +/-2.4 years; 81 men and 51 women in the control group, age 53.3 + -7 years, weight 72.6 + -10 kg, VAS score 5.0986 + -1.3812, and course 3.0 + -2.3 years. The two groups have no significance and good comparability in the aspects of sex, age, weight and disease course.
2. Method of producing a composite material
2.1 sources of drugs
Therapeutic agents: prepared according to the method in the embodiment 1;
control drug: remifentanil hydrochloride for injection (2 mg remifentanil hydrochloride (calculated as remifentanil) powder injection, Jiangsu Enhua pharmaceutical industry Co., Ltd.).
2.2 treatment protocol: after the local skin is disinfected conventionally, the upper limit of the external buttocks of the patient is intramuscular injection for 1 branch/1 time/d and is continuously injected for 7 days, and the treated group and the control group are added with 2 ml/branch of injection water each time. The therapeutic effect was evaluated after withdrawal of the drug. No other treatment measures are used during the treatment.
2.3 Observation items
2.3.1 safety observations: blood, urine and stool are tested conventionally. And (4) liver and kidney function examination.
2.3.2 therapeutic efficacy observations:
2.3.3 indexes of analgesic effect: the pain intensity is measured by VAS method, 0 means no pain, 1-3 means mild pain, 4-6 means moderate pain, and more than 7 means severe pain. The patient records before and 1-7 days after the drug administration.
3. Results
3.1 treatment effect evaluation standard (refer to related documents: the treatment effect is comprehensively evaluated at the end of a clinical treatment effect evaluation test, namely the ineffective effect is that the clinical symptoms and physical signs are improved by less than 30 percent, the effective effect is that the clinical symptoms and physical signs are improved by more than or equal to 30 percent and less than 75 percent, and the effective effect is that the clinical symptoms and physical signs are improved by more than or equal to 75 percent.
3.2 assay of therapeutic efficacy
3.2.1 comparison of VAS scores before and after treatment in two groups: see table 8:
| group of | Before treatment | After treatment |
| Treatment group | 5.1578±1.3187 | 1.0071±0.2124 |
| Control group | 5.1988±1.4824 | 1.9868±0.2872 |
3.2.2 comparison of pain conditions before and after treatment in two groups: see table 9.
TABLE 9 comparison of pain conditions before and after treatment in two groups
3.2.2 two groups of clinical curative effect comparison: see table 10.
TABLE 10 comparison of the clinical effects of the two groups
From the above results, it can be seen that the comparison of VAS scores before and after two groups of treatment, pain conditions before and after two groups of treatment and clinical effects of two groups, the treatment groups are superior to the control group, i.e. the freeze-dried preparation prepared by the invention is superior to the powder injection in the prior art.
The above tests were also performed on the lyophilized formulations and aerosols prepared in the other examples of the present invention, and similar results were obtained.
EXAMPLE 16 anesthetic analgesic Effect of Compounds of formula (I) (R is methyl) with remifentanil and nalbuphine, respectively
The test adopts a SD rat photothermal tail flick model, and uses the SD rat tail flick incubation period as an index to evaluate the analgesic effect of the tested medicine on pain caused by photothermal stimulation. The experimental animals are divided into 6 groups according to a random number table, namely a normal saline group A, a compound formula (I) group B, a remifentanil group C, a nalbuphine group D, a formula (I) + remifentanil group E and a formula (I) + nalbuphine group F, and 20 animals are respectively selected in each group. Wherein group A is a negative control group, B, C, D three groups are positive control groups, E, F is a test sample group, animals except group A are intravenously administered with 3mg/kg corresponding drugs, and group A is intravenously administered with normal saline with corresponding volume. E. The group F medicines are mixed according to the ratio of 1:1 and then used. On the day of the experiment, SD rats were housed in specially prepared fixed buckets with the tails exposed to the outside and were marked with light stimulation points applied with a marker pen to the lower 1/3 of the tails prior to the experiment. During testing, the marking point at the tail of the rat is aligned to the light hot point, photo-thermal stimulation is carried out after the animal is calm, when pain occurs, the animal has tail flick, and the tail flick incubation period of the rat is recorded in seconds. The above assays were performed before dosing (baseline latency) and before and 5, 15, 30min after dosing, respectively. The experimental results are shown in tables 1 and 2, and it can be seen from tables 1 and 2 that the analgesic effect of the compound formula (I) group combined with remifentanil is stronger than that of the compound formula (I) and remifentanil when used alone; after the compound shown in the formula (I) is used with nalbuphine, the onset time is shorter than that when the nalbuphine is used alone, and the analgesic effect time is longer than that when the nalbuphine is used alone.
TABLE 11 mean value(s) of photothermal tail flick experiment for rat (mean. + -. sem)
| 0min | 5min | 15min | 30min | |
| Physiological saline group | 5.23±0.81 | 5.31±0.78 | 4.91±0.52 | 4.87±0.59 |
| Compounds of formula (I) | 5.42±0.63 | 15.62±1.31 | 10.36±0.95 | 4.92±0.48 |
| Remifentanil group | 5.55±0.65 | 14.70±2.27 | 8.22±2.05 | 3.92±2.03 |
| Nalbuphine group | 5.40±0.45 | 5.21±1.47 | 15.23±1.26 | 15.01±0.48 |
| Formula (I) + remifentanil group | 6.26±0.43 | 20.24±1.47 | 10.32±1.55 | 3.21±1.66 |
| Formula (I) + nalbuphine group | 5.26±0.53 | 16.62±0.95 | 16.15±1.73 | 16.35±1.67 |
TABLE 12 photothermal tail flick experiment of rats effective percentage (%)
| 5min | 15min | 30min | |
| Compounds of formula (I) | 90％ | 10％ | 0％ |
| Remifentanil group | 90％ | 10％ | 0 |
| Nalbuphine group | |||
| 0％ | 90％ | 90％ | |
| Formula (I) + remifentanil group | 95％ | 15％ | 0％ |
| Formula (I) + nalbuphine group | 90％ | 90％ | 90％ |
The above tests were also performed on the powder injection preparations and aerosol preparations obtained in other examples 2 to 9 of the present invention, and similar results were obtained.
EXAMPLE 17 Effect of Compounds of formula (I) (R is methyl) on rat respiratory System in combination with remifentanil and nalbuphine, respectively
The SD rats are divided into 6 groups according to a random number table, namely a normal saline group A, a compound formula (I) group B, a remifentanil group C, a nalbuphine group D, a formula (I) + remifentanil group E and a formula (I) + nalbuphine group F, and each group comprises 8 rats. Wherein group A is a negative control group, group B, C, D is a positive control group, and group E, F is a test sample group. Animals in each of the groups except group A were given 3mg/kg of the corresponding drug intravenously, and group A was given a corresponding volume of physiological saline intravenously. And (3) acquiring, recording and analyzing the data of the experimental animals by using a Power Lab data acquisition system to obtain the respiratory frequency and the respiratory time of each group of experimental animals before administration and after administration for 5min, 15min and 30 min. The experimental results are shown in fig. 1 and fig. 2, and it can be seen from fig. 1 and fig. 2 that the compound group of formula (I) can reduce the respiratory frequency inhibition effect of remifentanil and nalbuphine and effectively improve the expiration time period when used together with remifentanil and nalbuphine, compared with the remifentanil group and nalbuphine group which are used alone.
The above tests were also performed on the powder injection preparations and aerosol preparations obtained in other examples 2 to 9 of the present invention, and similar results were obtained.
According to the test results, the narcotic analgesic pharmaceutical composition prepared by adopting the prescription and the process can effectively overcome the adverse reaction generated by the compound of the formula (I); meanwhile, the anesthesia analgesic effect of the opioid can be enhanced and prolonged, the discomfort and adverse reactions of injection pain, respiratory depression, constipation, nausea and vomiting and the like of the patient are effectively reduced, and the medication compliance of the patient is obviously improved; the pain of the patient in the operation process, fear and mental stress caused by viscera traction can be effectively eliminated, so that the physical and mental health of the patient is protected, the smooth implementation of the operation is facilitated, and the operation satisfaction of the patient is improved; when the compound composition is used for preparing a freeze-dried powder preparation, the opioid can be obviously found to inhibit the generation of impurity A in the process of preparing the compound composition shown in the formula (I), and the compound shown in the formula (I) also improves the stability of the opioid. In addition, the preparation process is simple, is more suitable for large-scale production requirements, and can ensure that the product quality meets the requirements.
Claims (4)
1. A method for preparing a narcotic analgesic pharmaceutical composition, comprising the steps of:
(1) adding the freeze-drying protective agent into water for injection to be dissolved, and adjusting the pH value of the solution to 2.5-4.5 by using a pH regulator;
(2) adding the raw materials of the narcotic analgesic composition, and stirring until the raw materials are completely dissolved;
(3) dissolving, namely adding medicinal carbon according to the weight volume ratio of 0.01-0.2%, stirring and adsorbing for 10-50 minutes, decarbonizing and filtering by using a 0.45 mu m filter membrane, sterilizing and filtering by using a 0.22 mu m filter membrane, filling and plugging, and then carrying out freeze drying, wherein the freeze drying process comprises the following steps:
(1) a pre-freezing stage: filtering the filled solution, putting the solution into a freeze-drying cabinet, starting a freeze dryer, refrigerating the front box, and keeping the temperature of the frozen product at-30 ℃ to-45 ℃ for 1-5 hours;
(2) a sublimation drying stage: vacuumizing, maintaining the vacuum of the front box between 10 and 50pa, and slowly heating to ensure that the temperature of the frozen product is not higher than 15 ℃ before sublimation drying is finished;
(3) and (3) analysis and drying stage: heating the frozen product to maintain the temperature of the frozen product at 20-25 ℃ for 5-18 h;
(4) after the prefreezing stage, the sublimation drying stage and the analysis drying stage are finished, the machine is shut down, the stopper is pressed, the anesthesia analgesic drug composition is taken out of the cabinet and the cover is rolled, wherein the anesthesia analgesic drug composition is a compound composition prepared by a compound shown in the formula (I) and opioid drugs,
in the formula (I), R is H, ethyl or isopropyl, the opioid comprises fentanyl, remifentanil, sufentanil, alfentanil, carfentanil, morphine, nalbuphine, hydromorphone, oxycodone and ropivacaine, the opioid inhibits the generation of impurity A in the compound shown in the formula (I) in the process of preparing the compound composition, and simultaneously the compound shown in the formula (I) enhances the stability of the opioid, and the impurity A is H, ethyl or isopropyl
In the formula (A), R is H, CH3Ethyl, or isopropyl.
2. The method for preparing a narcotic analgesic pharmaceutical composition as claimed in claim 1, wherein the pH of said solution is adjusted to 2.9 to 3.5 with a pH adjusting agent.
3. The method of claim 1, wherein the lyoprotectant is dextran, lactose, glycine, mannitol.
4. The method of claim 1, wherein the pH adjusting agent is hydrochloric acid, sodium hydroxide, or disodium hydrogen phosphate.
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| CN112402428B (en) * | 2020-11-26 | 2022-02-25 | 李依泽 | Application of remazolin in preparation of medicine for treating postoperative hyperalgesia induced by opioid |
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| CN103202815A (en) * | 2013-05-05 | 2013-07-17 | 王元青 | Injection for treating mental disease |
| CN103232454A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Medicine for treating mental disease |
| CN104146970A (en) * | 2013-05-05 | 2014-11-19 | 王元青 | Freeze-dried powder injection for treating mental disease |
| CN103347519B (en) * | 2010-11-08 | 2016-05-18 | Paion英国有限公司 | Use the dosage regimen that CNS 7056 (Lei meter Ma azoles logical sequence) is calm |
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| CN103347519B (en) * | 2010-11-08 | 2016-05-18 | Paion英国有限公司 | Use the dosage regimen that CNS 7056 (Lei meter Ma azoles logical sequence) is calm |
| CN103202815A (en) * | 2013-05-05 | 2013-07-17 | 王元青 | Injection for treating mental disease |
| CN103232454A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Medicine for treating mental disease |
| CN104146970A (en) * | 2013-05-05 | 2014-11-19 | 王元青 | Freeze-dried powder injection for treating mental disease |
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