CN115463084A - Compound oil solution preparation for long-acting analgesia and preparation method thereof - Google Patents
Compound oil solution preparation for long-acting analgesia and preparation method thereof Download PDFInfo
- Publication number
- CN115463084A CN115463084A CN202210502085.8A CN202210502085A CN115463084A CN 115463084 A CN115463084 A CN 115463084A CN 202210502085 A CN202210502085 A CN 202210502085A CN 115463084 A CN115463084 A CN 115463084A
- Authority
- CN
- China
- Prior art keywords
- oil
- dexamethasone
- ropivacaine
- formulation
- preparation
- 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
Images
Classifications
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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]
Abstract
The invention discloses a compound oil solution preparation for long-acting analgesia, which comprises ropivacaine or salts thereof, dexamethasone or esters thereof, phospholipid, ethanol and oil for injection, wherein the concentration of the ropivacaine is 1.0-5.0% (w/w) in terms of the ropivacaine, and the concentration of the dexamethasone or esters thereof is 0.005-0.5% (w/w) in terms of the dexamethasone. The invention provides a long-acting analgesic compound preparation which has simple preparation process and low cost and is convenient for industrial production.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and relates to a compound oil solution preparation for long-acting analgesia and a preparation method thereof.
Background
For the problem of moderate and severe pain after operation, analgesics and local anesthetics (local anesthetics for short) are mainly used for anesthesia clinically. The former can realize large-scale anesthesia, but has more obvious side effect and higher danger; the latter drug effect plays a targeted role accurately, but the action time is short, generally not more than 12h, and the application is limited. Clinically desirable pain relief times are typically several days or longer, so that it is difficult to achieve clinically desirable pain treatment times with a single administration. In order to meet clinical requirements, the analgesic time of the drug is usually prolonged by increasing the concentration or dosage of the local anesthetic, repeating multiple administration, implantation in a catheter body, nerve destruction and other technologies, but too many administration times bring great inconvenience to patients, and can also cause drug accumulation to cause local anesthetic poisoning; the use of intracorporeal catheter implantation not only requires expensive equipment and continuous monitoring, but also is prone to complications such as catheter blockage, catheter breakage and infection.
In terms of long-acting analgesic formulation development, the FDA approved bupivacaine liposome injection suspension (trade name EXPAREL) developed by Pacira pharmaceutical co. The bupivacaine in the EXPAREL can realize the slow release effect of more than 48h, and solves the clinical pain point of the conventional preparation. However, the liposome has a multivesicular structure, and the preparation process is more complicated than that of the conventional liposome, and the production cost is very high.
Ropivacaine is a novel long-acting amide local anesthetic, has higher sensitivity to C nerve fibers than A fibers, and shows obvious phenomena of motor nerve block and sensory nerve block separation. The action mechanism of ropivacaine is the same as that of local anesthetics such as procaine, lidocaine and bupivacaine, and the ropivacaine plays a role by inhibiting sodium ion channels of nerve cells and blocking nerve excitation and conduction. A large number of clinical research results show that ropivacaine has more extensive clinical application in the future due to the unique physicochemical characteristics of ropivacaine, namely obvious separation of sensory-motor nerve blocks at low concentration, exact treatment effects of anesthesia and pain, low cardiac toxicity, long action time and the like.
Dexamethasone is a long-acting glucocorticoid, the half-life of which is more than 36h, plays a vital role in the compound medicine for treating various acute and chronic pains, and obtains exact clinical effect. The peripheral nerve block is compounded and locally applied with dexamethasone, so that the analgesic time can be prolonged. 4-8 mg of dexamethasone is added into the local anesthetic, so that the sensory blocking time of the target nerve can be prolonged to several hours, even 10 hours. The mechanism of prolonging the blocking time by locally adding dexamethasone during nerve blocking is not completely understood, and at present, the dexamethasone is mainly considered to reduce the activity of C nerve fibers, directly inhibit the potassium channel activity of nerves and generate a local vasoconstriction effect and a systemic anti-inflammatory effect.
Research shows that the effect of prolonging the sensory nerve block time by combining ropivacaine and dexamethasone is not obvious. This is because the acidic environment of ropivacaine becomes alkaline after mixing the ropivacaine hydrochloride aqueous solution with the dexamethasone sodium phosphate aqueous solution just before use, and crystallization occurs 15 seconds after mixing, and the drug effect is reduced (Baeriswyl M, kirkham KR, jacot-Guillarmod A, et al. Effective of pereral vs. systematic chemical method to locking and ingredient a after-market new block: a systematic review and metal-analysis. Br J Anaesth.2017,1 (2): 183-191.
Therefore, a ropivacaine-dexamethasone compound preparation which does not need to be prepared temporarily is needed clinically.
Patent CN108743952A discloses a sustained release preparation of local anesthetic using phospholipid-miscible oil as carrier, said preparation further comprises antioxidant, said local anesthetic is selected from one or mixture of bupivacaine or ropivacaine free base. However, the formulation has a high miscibility agent ratio and presents a certain safety risk.
Xuyan et al (preparation of ropivacaine-dexamethasone acetate PLGA microspheres and in-vitro drug release characteristic research), xuyan et al (pharmaceutical guidance, 2009,28 (011): 1427-1431.) prepared a ropivacaine-dexamethasone acetate PLGA microsphere, but the preparation process of the preparation is complex and the technical difficulty is high.
Foley P L et al ("A chitosan thermal for delivery of neuropaine in regional mucosuloseal and rest height", foley P L et al, "Biomaterials", 2013,34 (10): 2539-2546.) prepared ropivacaine base nanoparticles and embedded with dexamethasone using a chitosan thermogel delivery system to enhance nerve block, but this formulation has the drawback of difficult process scale-up.
In view of the technical current situation, it is necessary to develop a long-acting analgesic compound preparation with simple preparation process, low cost, convenient industrial production and high safety.
Disclosure of Invention
The invention aims to provide a long-acting analgesic compound preparation which has simple preparation process and low cost and is convenient for industrial production, and the invention specifically comprises the following components:
the invention provides a compound oil solution preparation for long-acting analgesia, which comprises ropivacaine or salts thereof, dexamethasone or esters thereof, phospholipid, ethanol and oil for injection, wherein the concentration of the ropivacaine is 1.0-5.0% (w/w), preferably 3.0-5.0%, optimally 4.0% calculated by the ropivacaine, and the concentration of the dexamethasone or esters thereof is 0.005-0.5% (w/w), preferably 0.01-0.3%, optimally 0.03-0.1% calculated by the dexamethasone.
In the present invention, as one of the embodiments, the dexamethasone or the ester thereof is selected from dexamethasone, dexamethasone palmitate, dexamethasone acetate, dexamethasone isonicotinate, or dexamethasone dipropionate; dexamethasone palmitate is preferred.
In the present invention, as one of the embodiments, the ropivacaine or a salt thereof is selected from ropivacaine, ropivacaine hydrochloride, or ropivacaine mesylate; ropivacaine hydrochloride is preferred.
In one embodiment of the present invention, the phospholipid is used in an amount of 38.8 to 50.0% (w/w), preferably 45.0 to 50.0%, and most preferably 46.0%.
In the present invention, as one embodiment, the phospholipid is a mixture containing Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE). In one embodiment, the composition may further comprise Lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), sphingomyelin, phosphatidylglycerol, or phosphatidylinositol, or one or more thereof.
In one embodiment of the present invention, the phospholipid contains 96% or more of Phosphatidylcholine (PC), and more preferably the content of phosphatidylcholine in the phospholipid is 96% to 98%.
In one embodiment of the present invention, the phospholipid is selected from lecithin, egg yolk lecithin, high purity or refined egg yolk lecithin, soybean phospholipid, refined soybean phospholipid, phosphatidylcholine, egg yolk phosphatidylcholine, polyene phosphatidylcholine, glycerol phosphatidylcholine, hydrogenated soybean phospholipid, hydrogenated egg yolk phospholipid, and one or more kinds thereof. As one embodiment, the phospholipid is preferably egg yolk lecithin, phosphatidylcholine, high purity or refined egg yolk lecithin, or one or more thereof. In one embodiment, the phospholipid is egg yolk lecithin or high-purity or refined egg yolk lecithin, or one or more of them. As an illustrative example, the phospholipid is selected from, for example, EPCS (high purity egg yolk lecithin, lipoid, germany), PL-100M (lecithin, nippon Hippocampus Co., ltd.), E80-SN (egg yolk lecithin, lipoid, germany), HSPC (hydrogenated soybean lecithin, nippon Kogyo Co., ltd.), PC-98T (phosphatidylcholine, nippon Hippon Hippocampus Co., ltd.), DOPE (phosphatidylethanolamine, nippon Hippocampus Co., ltd.), and the like.
In one embodiment of the present invention, the ethanol is anhydrous ethanol, and the amount of the ethanol is 5.0 to 20.0% (w/w), preferably 15.0 to 20.0%.
In one embodiment of the present invention, the amount of the oil for injection is 33.0 to 43.0% (w/w), preferably 34 to 35%.
In the present invention, as one of the embodiments, the oil for injection is selected from sesame oil, tea oil, soybean oil, sunflower seed oil, peanut oil, castor oil, corn oil, olive oil, medium chain triglyceride or cottonseed oil, or one or more thereof, preferably soybean oil, castor oil or medium chain triglyceride, or one or more thereof.
In the present invention, as one embodiment, the formulation further comprises a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprising an antioxidant.
In one embodiment of the present invention, the antioxidant is used in an amount of 0.02 to 1% (w/w), preferably 0.04 to 0.1%, more preferably 0.05 to 0.5%, and most preferably 0.1 to 0.5%.
In the present invention, as one embodiment, the antioxidant is selected from tocopherol, ascorbyl palmitate, dibutylphenol, t-butyl p-hydroxyanisole, cysteine or cysteine hydrochloride, or one or more of them.
In the present invention, as one embodiment, the formulation is prepared from
Or is made of
Or is made of
Or is made of
In the present invention, as one embodiment, the administration route of the preparation is intramuscular injection or smearing administration.
The present invention also provides a method of preparing any of the foregoing formulations, the method comprising:
(1) Weighing components except ropivacaine or salts thereof and dexamethasone or esters thereof, placing in a closed container, heating in water bath, stirring for dissolving to obtain blank oil solution;
(2) Adding ropivacaine or salts thereof and dexamethasone or esters thereof into the blank oil solution, heating in water bath, and stirring for dissolving to obtain a medicinal oil solution;
(3) Filtering the medicinal oil solution, bottling, charging nitrogen, and sealing.
In the method of the present invention, as one of embodiments, the method further comprises: heating in water bath at 70 ℃ in the step (1), and heating in water bath at 70 ℃ in the step (2).
In the method of the present invention, as one of the embodiments, the method further comprises: filtering the medicinal oil solution in the step (3) by using a filter membrane, preferably a filter membrane of 0.45 μm, 0.65 μm or 0.22 μm.
The invention has the following advantages:
(1) The phospholipid oil solution is used as a solvent, and the solvent system has a good slow release effect on the medicine and does not cause crystallization and precipitation of the medicine in the preparation;
(2) The long-acting analgesic effect is further enhanced by combining ropivacaine and dexamethasone;
(3) The preparation of the invention has simple preparation process, low cost, convenient industrial production and high safety.
Drawings
FIG. 1 is a graph of the change in body weight of the animals of example 8.
FIG. 2 is a graph showing the decrease rate (%) of the animal's postoperative paw withdrawal pressure value in example 8.
Detailed Description
The following examples and experimental examples are intended to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.
Example 1: (4% -0.125% preparation of Compound preparation)
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a sealed glass bottle, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in a water bath at 70 ℃, and stirring to dissolve to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Example 2 preparation of 4% -0.25% Compound preparation
| Prescription | Dosage of | Content (%, w/w) |
| Ropivacaine hydrochloride | 4.8 parts of | 4.0 (calculated as ropivacaine) |
| Dexamethasone palmitate | 0.4 portion of | 0.25 (calculated as dexamethasone) |
| EPCS | 46.0 portion | 46.0 |
| Castor oil | 33.7 parts of | 33.7 |
| Anhydrous ethanol | 15.0 parts of | 15.0 |
| Tocopherol | 0.1 part | 0.1 |
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a sealed glass bottle, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Comparative example 1 (preparation of dexamethasone 0.125% formulation)
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a sealed glass bottle, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding dexamethasone palmitate into the blank oil solution, heating in water bath at 70 deg.C, and stirring for dissolving to obtain medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Comparative example 2 (preparation of dexamethasone 0.25% formulation)
| Prescription | Dosage of | Content (%, w/w) |
| Dexamethasone palmitate | 0.4 portion of | 0.25 (calculated by dexamethasone) |
| EPCS | 46.0 portion | 46.0 |
| Castor oil | 38.5 portions of | 38.5 |
| Anhydrous ethanol | 15.0 parts of | 15.0 |
| Tocopherol | 0.1 part | 0.1 |
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a sealed glass bottle, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding dexamethasone palmitate into the blank oil solution, heating in water bath at 70 deg.C, and stirring for dissolving to obtain medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Example 3 preparation of 1% -0.1% Compound preparation
1) Weighing yolk lecithin, absolute ethyl alcohol, soybean oil and tert-butyl p-hydroxyanisole, placing in a sealed glass bottle, heating in water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Example 4-1 (preparation of 5% -0.5% Compound preparation)
| Prescription | Prescription | Content (%, w/w) |
| Ropivacaine hydrochloride | 6.0 parts of | 5.0 (in terms of ropivacaine) |
| Dexamethasone palmitate | 0.8 portion of | 0.5 (calculated as dexamethasone) |
| Egg yolk lecithin | 38.1 portions of | 38.1 |
| Soybean oil | 35.0 parts of | 35.0 |
| Anhydrous ethanol | 20.0 portion | 20.0 |
| Cysteine hydrochloride | 0.1 part | 0.1 |
1) Weighing yolk lecithin, absolute ethyl alcohol, soybean oil and cysteine hydrochloride, placing in a sealed glass bottle, heating in water bath at 70 ℃, and stirring for dissolving to obtain a blank oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in a water bath at 70 ℃, and stirring to dissolve to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
Example 4-2 (preparation of 5% -0.5% Compound preparation)
The preparation method was the same as that of example 4-1.
Example 5 examination of phospholipids in the formulation
The theoretical contents of PC and PE in the phospholipids of different kinds are as follows:
EPCS contains 96% of PC, 0.1% of PE, 1% of LPC (lysophosphatidylcholine) and 1% of sphingomyelin;
the PC content in PC-98T is 98%;
the PC content in PL-100M is 76%, and the PE content is 20%;
PE content in DOPE is 100%;
the content of PC in E80-SN is about 80%, and the content of PE is unknown;
the PC content in HSPC is about 100%.
The content of PC and PE is the percentage of PC or PE in the total weight of the solution.
Experimental methods (the following (1) to (3)):
compound preparations were prepared according to the recipe in the table, with reference to the method of "example 2":
1) Weighing the components except for the ropivacaine and the dexamethasone, putting the components in a closed glass bottle, heating the components in a water bath at 70 ℃, and stirring the components to dissolve the components to obtain a blank oil solution;
2) Adding ropivacaine and dexamethasone into the blank oil solution, heating in a water bath at 70 ℃, and stirring for dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, bottling, charging nitrogen, and sealing.
After standing, the properties of the drug oil solution were observed.
(1)
The prepared samples were placed at room temperature and examined for stability at 0, 5, and 10 days, with the following results:
and (4) conclusion: by using the phospholipids EPCS, PL-100M, E80-SN, HSPC, PC-98T for the preparation of ropivacaine hydrochloride oil solution, it was found from the results that ropivacaine hydrochloride oil solution can be prepared using the phospholipids PC-98T and EPCS, while the solution prepared using the phospholipid EPCS is more stable.
(2) The proportion of PC is controlled by adjusting the dosage of EPCS:
the prepared samples were placed at room temperature and examined for stability at 0, 5, and 10 days, with the following results:
and (4) conclusion: from the above results, firstly, as the amount of phospholipid increases, the content of oil for injection decreases, the stability of the solution increases, the amount of phospholipid is 38.8% -50%, and all solutions generate crystallization at day 10, through further investigation, when the amount of phospholipid in the solution is 46%, the solution still does not generate crystallization after being placed for 21 days, the stability is better, and in order to further investigate the stability of the solution, the solution still does not generate crystallization after being placed at 4-8 ℃ for refrigeration for 180 days; secondly, from the above results, it is understood that the stability of the solution is best when the PC content in the solution is 38% to 47.86%.
(3) By adjusting the dosage of EPCS and PL-100M in the prescription, the proportion of PC and PE is controlled,
and (4) conclusion: from the above results, it is understood that the content of PE in the solution also has a certain influence on the stability of the solution, and when the content of PE is 2.04%, the solution is crystallized when left for 5 days, when the content of PE is less than or equal to 0.643%, the stability of the solution is further improved, and when the content of PE is less than or equal to 0.245%, the stability of the solution is significantly improved.
EXAMPLE 6 investigation of ropivacaine in the prescription
Replacement of ropivacaine hydrochloride with ropivacaine:
the experimental method comprises the following steps:
the compound preparation is prepared according to the prescription in the table, and the preparation is carried out according to the method of 'example 2':
1) Weighing the components except for the ropivacaine and the dexamethasone, putting the components in a closed glass bottle, heating the components in a water bath at 70 ℃, and stirring the components to dissolve the components to obtain a blank oil solution;
2) Adding ropivacaine and dexamethasone into the blank oil solution, heating in a water bath at 70 ℃, and observing the dissolution condition of the system.
And (4) conclusion: replacing ropivacaine hydrochloride with ropivacaine using the same adjuvants and amounts as in batch number 210130-4, the results show that ropivacaine hydrochloride is more suitable than ropivacaine for the preparation of oil solutions.
Example 7 comparative test of drug efficacy
7.1 purpose of the test
The compound preparation of ropivacaine and dexamethasone and the single preparation of dexamethasone have the inhibiting effect on the plantar pain of rats.
7.2 sample information
| Group of | Ropivacaine concentration (%, w/w) | Dexamethasone concentration (%, w/w) |
| Example 1 | 4.0 | 0.125 |
| Example 2 | 4.0 | 0.25 |
| Comparative example 1 | 0.0 | 0.125 |
| Comparative example 2 | 0.0 | 0.25 |
7.3 design of experiment
7.3.1 test animal information: SD rats, male, SPF grade, 200-220g,30, purchased from Kyoto Hua laboratory animal technology, inc. of Beijing Wintoli. Quality certification of experimental animals: no:11001120011003207; license number: SCXK (Ko) 2016-0006.
7.3.2 grouping and administration
7.3.3 dose setting basis
The measurement time is to measure the foot lifting tolerance of the animal according to the preparation-related information of 0h, 2h, 4h and 6h respectively and observe the duration time of the drug effect.
7.4 test procedure
7.4.1 animal feeding
The temperature of the breeding room is 22 +/-3 ℃, the humidity is 40-70%, the light and the shade alternate for 12h, and the animals can freely take food and drink water.
7.4.2 test procedure
1) The day before the experiment was randomly grouped according to the grouping rules in the scheme.
2) The left hind foot lifting tolerance of 0h rats was measured. The rat is placed in a detection cage to adapt to the environment for 20min, the middle part of the pelma of the hind limb to be detected is slowly and softly stimulated by a probe of a pain instrument after the rat is no longer observed and calm, if the rat rapidly generates a foot contraction reaction due to stimulation, data are measured and recorded, and if the rat generates the foot contraction reaction due to the body movement of the rat, the data are not calculated. The measurement was repeated and the results were recorded.
3) 0.05mL of the test sample was extracted with a 1mL syringe and injected intramuscularly from the left hind sole of the rat.
4) The left hind paw of the rat was tested for foot lifting tolerance at 2h, 4h and 6h after administration as described in step 2).
7.5 data processing and statistical analysis method:
the elevated foot tolerance of each group of animals was compared to the model group using an independent sample t test of Excel 2010, with a significant difference of p < 0.05.
7.6 test results
| Example 1 | Example 2 | Comparative example 2 | Comparative example 1 | |
| Time (h) | Resistance to foot lifting | Resistance to foot lifting | Resistance to foot lifting | Resistance to foot lifting |
| 0 | 24.7 | 27.7 | 28.5 | 31.1 |
| 2 | 100.0 | 100.0 | 100.0 | 100.0 |
| 4 | 100.0 | 100.0 | 100.0 | 87.2 |
| 6 | 55.1 | 100.0 | 32.5 | 15.9 |
7.7 conclusion
The single dexamethasone oil solution has relatively poor analgesic effect, the compound oil solution has relatively good analgesic effect, and the analgesic time is prolonged along with the increase of the concentration of dexamethasone.
Example 8 efficacy verification test
8.1 purpose of the test
Exploration example 2 analgesic Effect of Compound preparation on Beagle dog incision pain model
8.2 test design
8.2.1 test animals
Beagle dog, general grade, male, age 13-14 months, weight 9.65-11.64kg, 6, purchased from beijing marts biotechnology limited. License number: SCXK (Jing) 2016-0001, animal quality certification number: 1103181911000403.
8.2.2 grouping
6 male Begale dogs which are qualified for quarantine are randomly divided into 2 groups by reference weight after a basic value (inner side of left hind limb) is determined by a Von Frey method, 1 group is a model control group, 2 groups are test article groups (2 mL/dog), and 3 dogs are respectively selected.
8.2.3 Molding
Fasting overnight before the operation, on the day of the operation, injecting 1.0g of cefazolin sodium (the administration concentration is 0.25 g/mL) into veins before the operation and after the operation is finished; D2-D3, 0.5g of cefazolin sodium (administration concentration 0.25 g/mL) is injected intramuscularly. Using Shutai 50 (8 mg/kg) animals were anesthetized, a longitudinal incision was made in the medial thigh on the left side to make a 5-6 cm incision, and skin and hide were incisedAfter the fascia was removed, a longitudinal incision was made approximately 2cm deep in the medial thigh muscle at the incision. After the incision is finished, the incision is smeared according to the following table:
after the administration, the muscle and the skin are sutured in turn, and the iodophor is disinfected. Day 2-7 after operation, the wound was disinfected by iodophor every day, analgesic was given by intramuscular injection on day 4 after operation (72 h after last ethological test) to day 7 (0.4% w/v,0.05 mL/kg), and wound suture was removed on day 7.
8.2.4 dosing frequency and mode
The model control group (group 1) was not administered. The test article group (group 2) was administered with the compound preparation. Immediately after surgery (before closing the wound), a single wound application was administered with D1 on the day of first administration.
8.3 detection index
8.3.1 general clinical observations
The death or dying condition, mental state, behavior and activity of the animals are observed by cage side 2 times a day, and the wound healing condition of the animals is observed continuously for 7 days after the operation.
8.3.2 body weight
1 time before operation and 1 time at the end of the experiment.
8.3.3Von Frey test
And (3) detecting animals: all animals were used.
Detection time: 1-2 times before grouping, and 1 time after 1.5h, 3h, 6h, 8h, 12h, 24h, 30h, 48h and 72h after drug administration.
The detection method comprises the following steps: beagle dogs were fixed to pavlov sling 1 week earlier and acclimatized for approximately 30min per day. The minimum stimulator was selected and the instrument was held in the hand to apply a vertical and progressive force to the dog near the medial thigh wound until the animal developed an escape response and the value displayed on the screen was recorded.
Using an instrument: bioseb BIO-VELTALGO type pain measuring instrument.
Detection indexes are as follows: paw withdrawal pressure value decline rate (%) = (pre-operative base-test value)/pre-operative base value.
8.4 test results
8.4.1 general clinical observations
No obvious abnormality was observed during the experiment.
8.4.2 body weight
The body weight of the model control group is similar to that of the test sample group before operation (10.34 plus or minus 1.12vs 10.37 plus or minus 0.74kg, P is more than 0.05); the body weights of the two groups remained similar at the end of the experiment (D8) (10.00. + -. 1.35vs 10.20. + -. 0.87kg, P0.05). The change of the animal body weight is shown in figure 1, and no obvious abnormality is seen.
8.4.3 claw shrinkage pressure value
The decrease rate of the paw withdrawal pressure value of the model control group animal after the operation fluctuates little and fluctuates between (60.2 +/-8.9)% and (71.7 +/-6.3)%.
After the medicine is applied for 1.5 to 72 hours, the rate of decline of the paw withdrawal pressure value of the test group animals after the operation is less than that of the model control group; compared with a model control group, the rate of decline of the paw-contracting pressure value of the test sample group is obviously reduced (P is less than 0.05-P is less than 0.01) after the test sample group is applied for 8-30 hours.
The change of the reduction rate (%) of the animal's postoperative paw withdrawal pressure value is shown in FIG. 2.
The decrease rate fluctuation of the postoperative paw withdrawal pressure value of the model control group animals is small. Compared with a model control group, the rate of decline of the paw-contracting pressure value of the test sample group is obviously reduced (P is less than 0.05-P is less than 0.01) after the test sample group is applied for 8-30 hours.
8.5 conclusion
2mL of compound preparation (preparation in example 2) is applied in each wound in a smearing way, so that the drop of the paw withdrawal pressure value caused by the incision pain of the Beagle dog can be obviously improved, and the duration time of the drug effect is not less than 48h.
Claims (19)
1. The compound oil solution preparation for long-acting analgesia is characterized by comprising ropivacaine or salts thereof, dexamethasone or esters thereof, phospholipid, ethanol and oil for injection, wherein the concentration of the ropivacaine is 1.0-5.0% (w/w), preferably 3.0-5.0%, optimally 4.0% calculated by the ropivacaine, and the concentration of the dexamethasone or esters thereof is 0.005-0.5% (w/w), preferably 0.01-0.3%, optimally 0.03-0.1% calculated by the dexamethasone.
2. The formulation of claim 1, wherein the dexamethasone or ester thereof is selected from dexamethasone, dexamethasone palmitate, dexamethasone acetate, dexamethasone isonicotinate, or dexamethasone dipropionate; dexamethasone palmitate is preferred.
3. A formulation according to claim 1, wherein the ropivacaine or salt thereof is selected from ropivacaine, ropivacaine hydrochloride, or ropivacaine mesylate; ropivacaine hydrochloride is preferred.
4. The formulation according to claim 1, characterized in that the amount of phospholipids is 38.8-50.0% (w/w), preferably 45.0-50.0%, optimally 46.0%.
5. A formulation as claimed in claim 4 wherein the phospholipids are a mixture comprising Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE).
6. The formulation of claim 5, wherein the phospholipid further comprises one or more of Lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), sphingomyelin, phosphatidylglycerol, or phosphatidylinositol.
7. A preparation according to claim 6, wherein the phospholipid comprises more than 96% Phosphatidylcholine (PC), more preferably wherein the content of phosphatidylcholine in the phospholipid is 96-98%.
8. The formulation of claim 4, wherein the phospholipid is selected from the group consisting of lecithin, egg yolk lecithin, high purity or refined egg yolk lecithin, soybean phospholipid, refined soybean phospholipid, phosphatidylcholine, egg yolk phosphatidylcholine, polyene phosphatidylcholine, glycerol phosphatidylcholine, hydrogenated soybean phospholipid or hydrogenated egg yolk phospholipid, or one or more thereof; preferably egg yolk lecithin, phosphatidylcholine, high purity or refined egg yolk lecithin, or one or more of them; further preferably egg yolk lecithin or high-purity or refined egg yolk lecithin, or one or more of them; even further preferred are EPCS, PL-100M, E80-SN, HSPC, PC-98T or DOPE, or one or more thereof.
9. The formulation according to claim 1, characterized in that the ethanol is absolute ethanol, in an amount of 5.0-20.0% (w/w), preferably 15.0-20.0%.
10. The formulation according to claim 1, wherein the amount of the oil for injection is 33.0-43.0% (w/w), preferably 34-35%.
11. The formulation according to claim 10, wherein the injectable oil is selected from sesame oil, tea oil, soybean oil, sunflower oil, peanut oil, castor oil, corn oil, olive oil, medium chain triglycerides or cottonseed oil, or one or more thereof; preferably soybean oil, castor oil or medium chain triglycerides, or one or more thereof.
12. The formulation of any one of claims 1 to 11, wherein the formulation further comprises a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises an antioxidant.
13. The formulation according to claim 12, characterized in that the antioxidant is used in an amount of 0.02-1% (w/w), preferably 0.04-0.1%, more preferably 0.05-0.5%, most preferably 0.1-0.5%.
14. The formulation of claim 11, wherein the antioxidant is selected from tocopherol, ascorbyl palmitate, dibutylphenol, t-butyl p-hydroxyanisole, cysteine, or cysteine hydrochloride, or one or more thereof.
15. The formulation of claim 12, which is prepared from
Or is made of
Or is made of
Or is made of
16. The preparation of claim 12, wherein the preparation is administered by intramuscular injection or by smearing.
17. A method of preparing a formulation according to any one of claims 1 to 16, said method comprising:
(1) Weighing components except for ropivacaine or salts thereof and dexamethasone or esters thereof, placing the components in a closed container, heating in water bath, and stirring for dissolving to obtain a blank oil solution;
(2) Adding ropivacaine or salt thereof and dexamethasone or ester thereof into the blank oil solution, heating in water bath, and stirring for dissolving to obtain a medicinal oil solution;
(3) Filtering the medicinal oil solution, filling, charging nitrogen, and sealing.
18. The method of claim 17, further comprising: heating in water bath at 70 ℃ in the step (1), and heating in water bath at 70 ℃ in the step (2).
19. The method of claim 17, further comprising: filtering the medicinal oil solution in the step (3) through a filter membrane, preferably a filter membrane of 0.45 μm, 0.65 μm or 0.22 μm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021106472947 | 2021-06-10 | ||
| CN202110647294 | 2021-06-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115463084A true CN115463084A (en) | 2022-12-13 |
Family
ID=84364329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210502085.8A Pending CN115463084A (en) | 2021-06-10 | 2022-05-10 | Compound oil solution preparation for long-acting analgesia and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115463084A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104427976A (en) * | 2012-05-10 | 2015-03-18 | 佩因拉佛姆有限公司 | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof |
| CN104706574A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof |
| CN111388418A (en) * | 2018-12-31 | 2020-07-10 | 北京泰德制药股份有限公司 | Pharmaceutical composition containing ropivacaine or pharmaceutical salt thereof |
| CN111514099A (en) * | 2019-02-01 | 2020-08-11 | 北京蓝丹医药科技有限公司 | Aprepitant injection |
-
2022
- 2022-05-10 CN CN202210502085.8A patent/CN115463084A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104427976A (en) * | 2012-05-10 | 2015-03-18 | 佩因拉佛姆有限公司 | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof |
| CN104427977A (en) * | 2012-05-10 | 2015-03-18 | 佩因拉佛姆有限公司 | Depot formulations of local anesthetic and methods for preparation thereof |
| CN104706574A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof |
| CN111388418A (en) * | 2018-12-31 | 2020-07-10 | 北京泰德制药股份有限公司 | Pharmaceutical composition containing ropivacaine or pharmaceutical salt thereof |
| CN111514099A (en) * | 2019-02-01 | 2020-08-11 | 北京蓝丹医药科技有限公司 | Aprepitant injection |
Non-Patent Citations (1)
| Title |
|---|
| 张大志 等: "不同剂量地塞米松对罗哌卡因神经阻滞作用的影响", 临床麻醉学杂志, vol. 29, no. 3, pages 213 - 215 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108743952B (en) | Phospholipid-miscible solvent-oil sustained-release drug delivery system formula of local anesthetic and preparation method thereof | |
| US10206876B2 (en) | Depot formulations of a local anesthetic and methods for preparation thereof | |
| CN106999598B (en) | Stable cannabinoid formulations | |
| US10912772B2 (en) | Opioid formulations | |
| EP1809329B1 (en) | Sustained local anesthetic composition containing saib | |
| US20150250724A1 (en) | Long-lasting, controlled-release local anesthetic liposome preparation | |
| EP4091612A1 (en) | Long-acting ropivacaine pharmaceutical composition, preparation method therefor and use thereof | |
| WO2016066655A1 (en) | Injectable buprenorphine formulation | |
| AU2016244271B2 (en) | Opioid formulations | |
| DE3727585C2 (en) | Medicinal products containing nicorandil for external use | |
| EP3512495B1 (en) | Prostacyclin analogue formulations | |
| CN110327336B (en) | Mepivacaine xinafoate and long-acting sustained-release preparation thereof | |
| CN115463084A (en) | Compound oil solution preparation for long-acting analgesia and preparation method thereof | |
| US11672863B2 (en) | Enhanced solubility drug-containing formulations | |
| CN111388418B (en) | Pharmaceutical composition containing ropivacaine or pharmaceutical salt thereof | |
| CN108430454A (en) | Fulvestrant composition | |
| EP1143962B1 (en) | Parenteral solution of propofol (2,6-diisoprophylphenol) and 2.5-di-0-methyl-1.4;3.6-dianhydro-d-glucitol as a solvent | |
| WO2022175974A1 (en) | Non-aqueous injectable composition for sustained release of buprenorphine and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |