CN115463084B - 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 PDF

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CN115463084B
CN115463084B CN202210502085.8A CN202210502085A CN115463084B CN 115463084 B CN115463084 B CN 115463084B CN 202210502085 A CN202210502085 A CN 202210502085A CN 115463084 B CN115463084 B CN 115463084B
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dexamethasone
oil
ropivacaine
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CN115463084A (en
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张志兵
卢迪
甘乐凌
李显
冯德月
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Beijing Tide Pharmaceutical Co Ltd
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    • 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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    • A61K31/573—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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention discloses a compound oil solution preparation for long-acting analgesia, which comprises ropivacaine or salt thereof, dexamethasone or ester thereof, phospholipid, ethanol and oil for injection, wherein the concentration of the ropivacaine is 1.0-5.0% (w/w) based on ropivacaine, and the concentration of the dexamethasone or ester thereof is 0.005-0.5% (w/w) based on dexamethasone. The invention provides a long-acting analgesic compound preparation which has simple preparation process, low cost and convenient industrial production.

Description

Compound oil solution preparation for long-acting analgesia and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a compound oil solution preparation for long-acting analgesia and a preparation method thereof.
Background
Aiming at the problem of moderately severe pain after operation, analgesic and local anesthetic (local anesthetic for short) are mainly used for anesthesia clinically. The former can realize large-scale anesthesia, but has obvious side effects and high risk; the drug effect of the latter plays a role in targeting accurately, but the action time is relatively short and is generally not more than 12 hours, and the application is limited. Clinically desirable analgesic times are typically several days or longer, so it is difficult to achieve clinically desirable pain treatment times with a single administration. In order to meet clinical demands, the analgesic time of the medicine is often prolonged by increasing the concentration or dosage of local anesthetic, repeating the administration for a plurality of times, implanting in a catheter body, performing nerve destruction and other technologies, but excessive administration times bring great inconvenience to patients, and cause medicine accumulation and local anesthetic poisoning; the use of in vivo 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, 11 months 2011, the us FDA approved Pacira bupivacaine liposome injection suspension (trade name EXPAREL) developed by pharmaceutical limited for direct injection to the surgical site to help control postoperative pain. The bupivacaine in EXPAREL can realize the slow release effect for more than 48 hours, and solves the clinical pain point of the conventional preparation. However, the liposome has a multi-capsule structure, the preparation process is more complex than that of the conventional liposome, and the production cost is high.
Ropivacaine is a novel long-acting amide local anesthetic, has obviously higher sensitivity to C nerve fibers than to A fibers, and shows obvious separation phenomenon of motor nerve block and sensory nerve block. The mechanism of action of ropivacaine is the same as that of local anesthetics such as procaine, lidocaine, bupivacaine and the like, and the ropivacaine acts 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 unique physical and chemical properties, namely obvious separation on sensory-motor nerve block at low concentration, definite anesthesia and pain treatment effects, low cardiac toxicity, long acting time and the like, and is more widely applied to future clinic.
Dexamethasone is a long-acting glucocorticoid with a half-life longer than 36h, plays a vital role in compound medicine for treating various acute and chronic pains, and achieves exact clinical effects. Dexamethasone is locally used in the peripheral nerve block compound, so that the analgesic time can be prolonged. 4-8 mg of dexamethasone is added into the local anesthetic, so that the target nerve sensation blocking time can be prolonged to a plurality of hours, even 10 hours are unequal. The mechanism of locally adding dexamethasone to prolong the blocking time during nerve blocking is not completely known, and is mainly considered to be that the dexamethasone reduces the activity of C nerve fibers, directly inhibits the potassium channel activity of nerves and can generate local vasoconstriction and systemic anti-inflammatory effects at the same time.
Studies have shown that ropivacaine in combination with dexamethasone has no obvious effect in prolonging sensory nerve block time. The preparation method is characterized in that the ropivacaine hydrochloride aqueous solution and the dexamethasone sodium phosphate aqueous solution are mixed before use, the acidic environment where the ropivacaine is positioned is changed into alkaline environment, and crystals are separated out after 15 seconds of mixing, so that the efficacy is reduced (Baeriswyl M,Kirkham KR,Jacot-Guillarmod A,et al.Efficacy of perineural vs systemic dexamethasone to prolong analgesia after peripheral nerve block:a systematic review and meta-analysis.Br J Anaesth.2017,1;119(2):183-191).
Thus, there is a need for a ropivacaine-dexamethasone compound formulation that does not require clinical compounding.
Patent CN108743952a discloses a sustained release preparation of local anesthetic selected from bupivacaine or ropivacaine free base or a mixture of both, with phospholipid-miscible solvent-oil as carrier, which may further comprise an antioxidant. However, the mixed solvent in the preparation has high proportion, and certain safety risk exists.
Xu Yan et al ("preparation of ropivacaine-dexamethasone acetate PLGA microsphere and in vitro drug release characteristics study", xu Yan et al, "medical 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 great.
Foley P L et al ("A chitosan thermogel for delivery of ropivacaine in regional musculoskeletal anesthesia",Foley P L, biomaterials, 2013,34 (10): 2539-2546.) ropivacaine base nanoparticles were prepared and embedded with dexamethasone using a chitosan thermogel delivery system to enhance nerve blocking, but this formulation has the disadvantage of being difficult to scale up.
Aiming at the current state of the art, it is necessary to develop a long-acting analgesic compound preparation which has 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, low cost and convenient industrial production, and the specific invention is as follows:
The invention provides a compound oil solution preparation for long-acting analgesia, which comprises ropivacaine or salt thereof, dexamethasone or ester 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% based on ropivacaine, and the concentration of the dexamethasone or ester thereof is 0.005-0.5% (w/w), preferably 0.01-0.3%, optimally 0.03-0.1% based on dexamethasone.
In the present invention, as one of the embodiments, the dexamethasone or ester thereof is selected from dexamethasone, dexamethasone palmitate, dexamethasone acetate, dexamethasone isonicotinate, or dexamethasone dipropionate; preferably dexamethasone palmitate.
In the present invention, as one embodiment, the ropivacaine or a salt thereof is selected from ropivacaine, ropivacaine hydrochloride, or ropivacaine mesylate; ropivacaine hydrochloride is preferred.
In the present invention, the amount of the phospholipid is 38.8 to 50.0% (w/w), preferably 45.0 to 50.0%, and most preferably 46.0%, as one embodiment.
In the present invention, as one embodiment, the phospholipid is a mixture containing Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE). As one embodiment, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), sphingomyelin, phosphatidylglycerol, or phosphatidylinositol, or one or more thereof may be further contained.
In the present invention, as one embodiment, the phospholipid contains Phosphatidylcholine (PC) in an amount of 96% or more, and more preferably the content of phosphatidylcholine in the phospholipid is 96% to 98%.
In the present invention, as one embodiment, the phospholipid is selected from lecithin, egg yolk lecithin, high purity or refined egg yolk lecithin, soybean lecithin, refined soybean lecithin, phosphatidylcholine, egg yolk phosphatidylcholine, polyene phosphatidylcholine, glycerophosphorylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, or one or more thereof. As one embodiment, the phospholipid is preferably egg yolk lecithin, phosphatidylcholine, high purity or refined egg yolk lecithin, or one or more thereof. As one embodiment, the phospholipid is egg yolk lecithin or high-purity or refined egg yolk lecithin, or one or more of the above. As an exemplary illustration, the phospholipid is selected from, for example, EPCS (high purity egg yolk lecithin, german Lipoid), PL-100M (lecithin, japanese Qiubi Co., ltd.), E80-SN (egg yolk lecithin, german Lipoid), HSPC (hydrogenated soybean lecithin, japanese Severe Co., ltd.), PC-98T (phosphatidylcholine, japanese Qiubi Co., ltd.), DOPE (phosphatidylethanolamine, japanese Qiubi Co., ltd.), and the like.
In the present invention, as one embodiment, the ethanol is absolute ethanol in an amount of 5.0 to 20.0% (w/w), preferably 15.0 to 20.0%.
In the present invention, the amount of the oil for injection is 33.0 to 43.0% (w/w), preferably 34 to 35%, as one embodiment.
In the present invention, as one embodiment, 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 triglycerides or cottonseed oil, or one or more thereof, preferably soybean oil, castor oil or medium chain triglycerides, or one or more thereof.
In the present invention, as one of the embodiments, the formulation further comprises a pharmaceutically acceptable excipient comprising an antioxidant.
In 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%, as one embodiment.
In the present invention, as one embodiment, the antioxidant is selected from tocopherol, ascorbyl palmitate, dibutylphenol, tertiary butyl p-hydroxyanisole, cysteine or cysteine hydrochloride, or one or more thereof.
In the present invention, as one of the embodiments, the preparation consists of
Or by
Or by
Or by
In the present invention, as one embodiment, the administration route of the preparation is intramuscular injection or smear administration.
The invention also provides a method of preparing any of the foregoing formulations, the method comprising:
(1) Weighing components except ropivacaine or salt thereof, dexamethasone or ester thereof, placing in a closed container, heating in water bath, stirring for dissolving, and obtaining a blank oil solution;
(2) Adding ropivacaine or salt thereof, dexamethasone or ester thereof into the blank oil solution, heating in water bath, stirring and dissolving to obtain a medicinal oil solution;
(3) The medicinal oil solution is obtained by filtering, filling, nitrogen filling and sealing.
In the method of the present invention, as one of the embodiments, the method further comprises: and (3) heating in a water bath at 70 ℃ in the step (1), and heating in a water bath at 70 ℃ in the step (2).
In the method of the present invention, as one of the embodiments, the method further comprises: the drug oil solution in the step (3) is filtered through a filter membrane, preferably a 0.45 μm, 0.65 μm, or 0.22 μm filter membrane.
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 can not cause crystallization of the medicine in the preparation;
(2) The combination of ropivacaine and dexamethasone further enhances the long-acting analgesic effect;
(3) The preparation provided by the invention has the advantages of simple preparation process, low cost, convenience for industrial production and high safety.
Drawings
FIG. 1 is a graph showing the change in animal body weight of example 8.
FIG. 2 is a graph showing the change in the reduction rate (%) of the post-operative paw withdrawal pressure values of the animals of example 8.
Detailed Description
The following examples and experimental examples serve to further illustrate the invention but do not limit the effective scope of the invention in any way.
Example 1: (preparation of 4% -0.125% compound preparation)
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding nitrogen, and sealing.
Example 2 (preparation of 4% -0.25% Compound preparation)
Prescription of prescription Dosage of Content (%, w/w)
Ropivacaine hydrochloride 4.8 Parts of 4.0 (In ropivacaine)
Dexamethasone palmitate 0.4 Part 0.25 (In terms of dexamethasone)
EPCS 46.0 Parts 46.0
Castor oil 33.7 Parts 33.7
Absolute ethyl alcohol 15.0 Parts of 15.0
Tocopherols 0.1 Part 0.1
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding 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 closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding nitrogen, and sealing.
Comparative example 2 (preparation of dexamethasone 0.25% formulation)
Prescription of prescription Dosage of Content (%, w/w)
Dexamethasone palmitate 0.4 Part 0.25 (In terms of dexamethasone)
EPCS 46.0 Parts 46.0
Castor oil 38.5 Parts of 38.5
Absolute ethyl alcohol 15.0 Parts of 15.0
Tocopherols 0.1 Part 0.1
1) Weighing EPCS, absolute ethyl alcohol, castor oil and tocopherol, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding nitrogen, and sealing.
Example 3 (preparation of 1% -0.1% Compound preparation)
1) Weighing egg yolk lecithin, absolute ethyl alcohol, soybean oil and tert-butyl p-hydroxy anisole, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding nitrogen, and sealing.
Example 4-1 (preparation of 5% -0.5% Compound preparation)
Prescription of prescription Prescription of prescription Content (%, w/w)
Ropivacaine hydrochloride 6.0 Parts of 5.0 (In ropivacaine)
Dexamethasone palmitate 0.8 Part 0.5 (In terms of dexamethasone)
Egg yolk lecithin 38.1 Parts of 38.1
Soybean oil 35.0 Parts 35.0
Absolute ethyl alcohol 20.0 Parts 20.0
Cysteine hydrochloride 0.1 Part 0.1
1) Weighing egg yolk lecithin, absolute ethyl alcohol, soybean oil and cysteine hydrochloride, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding ropivacaine hydrochloride and dexamethasone palmitate into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding 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 investigation of phospholipids in the formulation
The theoretical contents of PC and PE in different phospholipids are as follows:
96% of PC, 0.1% of PE, 1% of LPC (lysophosphatidylcholine) and 1% of sphingomyelin in EPCS;
the PC content in PC-98T is 98%;
PC content 76% and PE content 20% in PL-100M;
PE content in DOPE is 100%;
the PC content in E80-SN is about 80%, and the PE content is not detailed;
the PC content in HSPC is about 100%.
Wherein the following components are used in parts by mass, and the content of PC and PE is the percentage of PC or PE in the total weight of the solution.
Experimental methods (following (1) to (3)):
The compound preparation is prepared according to the prescription in the table, and is prepared by the method of the example 2:
1) Weighing components except ropivacaine and dexamethasone, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Adding ropivacaine and dexamethasone into the blank oil solution, heating in water bath at 70 ℃, stirring and dissolving to obtain a medicinal oil solution;
3) Filtering the medicinal oil solution with 0.45 μm filter membrane, filling, adding nitrogen, and sealing.
After standing, the properties of the drug oil solution were observed.
(1)
The prepared samples were left at room temperature and their stability at 0, 5 and 10 days was examined, with the following results:
Conclusion: by using phospholipids EPCS, PL-100M, E, 80-SN, HSPC, PC-98T for the preparation of ropivacaine hydrochloride oil solutions, it was found from the results that ropivacaine hydrochloride oil solutions can be prepared using phospholipids PC-98T and EPCS, whereas the solution prepared using phospholipid EPCS has better stability.
(2) By adjusting the amount of EPCS, the proportion of PC is controlled:
The prepared samples were left at room temperature and their stability at 0, 5 and 10 days was examined, with the following results:
Conclusion: the above results show that, firstly, as the amount of phospholipid increases, the content of oil for injection decreases, the stability of the solution is enhanced, the amount of phospholipid is 38.8% -50%, the solution is crystallized on the 10 th day, and when the amount of phospholipid in the solution is 46%, the solution is still free from crystallization after being placed for 21 days, the stability is better, and in order to further examine the stability of the solution, the sample is placed at 4-8 ℃ and refrigerated for 180 days, the solution is still free from crystallization; secondly, from the above results, it is clear that the stability of the solution is optimal when the PC content in the solution is 38% -47.86%.
(3) By adjusting the dosage of EPCS and PL-100M in the prescription, the proportion of PC and PE is controlled,
Conclusion: from the above results, it is apparent that the PE content in the solution also has a certain effect on the stability of the solution, and when the PE content is 2.04%, the solution is crystallized when left for 5 days, and when the PE content is less than or equal to 0.643%, the stability of the solution is further improved, and when the PE content is less than or equal to 0.245%, the stability of the solution is significantly improved.
EXAMPLE 6 investigation of ropivacaine in the formulation
Ropivacaine hydrochloride is replaced by ropivacaine:
The experimental method comprises the following steps:
The compound preparation is prepared according to the prescription in the table, and is prepared by the method of the example 2:
1) Weighing components except ropivacaine and dexamethasone, placing in a closed glass bottle, heating in water bath at 70 ℃, stirring and dissolving to obtain a white oil solution;
2) Ropivacaine and dexamethasone are added into the blank oil solution, and the solution is heated in a water bath at 70 ℃ to observe the dissolution condition of the system.
Conclusion: replacing ropivacaine hydrochloride with ropivacaine using the same excipients and amounts as lot number 210130-4, the results indicate that ropivacaine hydrochloride is more suitable for use in the preparation of an oil solution than ropivacaine.
Example 7 comparative test of efficacy
7.1 Purpose of test
The inhibition effect of the single formulation of dexamethasone on rat plantar pain is compared with that of the compound formulation of ropivacaine and dexamethasone.
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 experiments
7.3.1 Test animal information: SD rats, male, SPF grade, 200-220g,30, purchased from Peking Vietnam Lihua animal technology Limited. Quality qualification certificate of experimental animal: no:11001120011003207; license number: SCXK (Beijing) 2016-0006.
7.3.2 Grouping and administration
7.3.3 Dose setting basis
The measurement time is to measure the tolerance of the animal to lift foot according to the relevant information of the preparation, namely 0h, 2h, 4h and 6h, and observe the duration of the drug effect.
7.4 Test procedure
7.4.1 Animal feeding
The temperature of the feeding room is 22+/-3 ℃, the humidity is 40-70%, the lamplight is changed in 12 hours, and the animals can freely take food and drinking 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 paw lifting tolerance of the 0h rat was measured. Placing the rat in a detection cage to adapt to the environment for 20min, slowly and gently stimulating the midfoot of the hind limb to be detected by using a pain instrument probe after the rat is no longer hopeful and calm, and recording data if the rat rapidly shows the foot shrinking reaction due to the stimulation, and not counting the foot shrinking reaction due to the physical activity of the rat. The results were repeatedly measured and recorded.
3) 0.05ML of the test sample was withdrawn by a 1mL syringe, and intramuscular injection was performed from the left rear sole of the rat.
4) The left hind paw of the rat was tested for resistance to lifting foot as described in step 2) for 2h, 4h and 6h post-dose.
7.5 Data processing and statistical analysis methods:
Independent sample t-test using Excel 2010 compares the foot lift tolerance of each group of animals to the model group, with p <0.05 being a significant difference.
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 dexamethasone concentration.
Example 8 efficacy verification test
8.1 Purpose of test
Exploring the analgesic effect of the Compound formulation of example 2 on the Beagle canine incision pain model
8.2 Design of experiments
8.2.1 Test animals
Beagle dogs, common grade, male, age 13-14 months, weight 9.65-11.64 kg,6, purchased from beijing masi biotechnology limited. License number: SCXK (Beijing) 2016-0001, animal quality eligibility number: 1103181911000403.
8.2.2 Grouping
6 Quarantine qualified male Begale dogs are randomly divided into 2 groups, wherein 1 group is a model control group, 2 groups are test article groups [ 2 mL/each ] and 3 reference weights are measured by a Von Frey method.
8.2.3 Moulding
Pre-operation fasted overnight, on the day of operation, 1.0g of cefazolin sodium (administration concentration 0.25 g/mL) was respectively injected intravenously before operation and after operation; D2-D3, 0.5g of cefazolin sodium (administration concentration 0.25 g/mL) was intramuscular-injected. Animals were anesthetized with sulte 50 (8 mg/kg), a longitudinal incision of about 5-6 cm was made on the inner side of the left thigh, and after incision of the skin and subcutaneous fascia, a longitudinal incision of about 2cm was made on the inner group of muscles of the thigh at the incision. The incision site is smeared and dosed according to the following table after the incision is completed:
After the administration, the muscle and the skin are sutured in sequence, and the iodophor is sterilized. The wound is disinfected by iodophor every day on the 2 th to 7 th days after operation, pain is relieved by intramuscular injection on the 4 th day (after 72h of final behavioural detection after medicine) to the 7 th day, and the wound suture line is removed on the 7 th day.
8.2.4 Frequency and mode of administration
Model control group (group 1) was not dosed. The test group (group 2) was given a compound preparation. Immediately after the operation (before the wound is closed), the single wound is smeared and administrated, and D1 is the day of the first administration.
8.3 Detection index
8.3.1 General clinical observations
Animals were observed 2 times per day by cage side for death or dying, mental status, behavioral activity, etc., and wound healing was observed 7 days continuously after surgery.
8.3.2 Body weight
Preoperative 1 time and experimental end 1 time.
8.3.3Von Frey test
Detecting animals: all animals.
Detection time: 1-2 times before grouping, 1.5 hours, 3 hours, 6 hours, 8 hours, 12 hours, 24 hours, 30 hours, 48 hours and 72 hours after medicine are measured 1 time each.
The detection method comprises the following steps: beagle dogs were fixed to pavlov's harness 1 week in advance and were acclimatized for about 30min each day. Selecting a minimum stimulator, holding an instrument handle, applying vertical and gradual force to the vicinity of the inner side wound of the thigh of the dog until the animal has an escape response, and recording the value displayed on the screen.
The instrument is used: bioseb BIO-VETALGO type pain measurer.
Detecting the index: reduction rate (%) = (preoperative basal value-test value)/preoperative basal value.
8.4 Test results
8.4.1 General clinical observations
No obvious abnormalities were observed during the experiment.
Weight of 8.4.2
The preoperative weights of the model control group and the test group are similar (10.34+/-1.12 vs 10.37+/-0.74 kg, P > 0.05); endpoint of experiment (D8) the two groups had similar body weights (10.00.+ -. 1.35 vs. 10.20.+ -. 0.87kg, P0.05). The change of the animal body weight is shown in fig. 1, and no obvious abnormality is seen.
8.4.3 Paw-retracting pressure value
The fluctuation of the reduction rate of the post-operation paw withdrawal pressure value of the animal in the model control group is smaller and is between (60.2+/-8.9)% and (71.7+/-6.3)%.
After 1.5-72 hours of the medicine, the reduction rate of the post-operation paw-shrinking pressure value of the animals in the test sample group is smaller than that of the model control group; compared with the model control group, the reduction rate 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 8-30 hours after the medicine.
The change of the reduction rate (%) of the paw withdrawal pressure value after the operation of the animal is shown in fig. 2.
The fluctuation of the reduction rate of the post-operation paw withdrawal pressure value of the animals in the model control group is small. Compared with the model control group, the reduction rate 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 8-30 hours after the medicine.
8.5 Conclusion
The reduction of the paw withdrawal pressure value caused by the incision pain of the Beagle dog can be obviously improved by applying 2 mL/compound preparation (the preparation of the example 2) in a single wound, and the duration of the drug effect is not less than 48 hours.

Claims (25)

1. A compound oil solution preparation for long-acting analgesia is characterized in that the preparation comprises ropivacaine or salt thereof, dexamethasone or ester thereof, phospholipid, ethanol and oil for injection, wherein,
The concentration of ropivacaine or salt thereof is 1.0-5.0% (w/w) based on ropivacaine;
the concentration of dexamethasone or ester thereof is 0.005-0.5% (w/w) based on dexamethasone;
The dosage of the phospholipid is 38.8-50.00% (w/w), and the phospholipid is egg yolk lecithin and contains phosphatidylcholine and phosphatidylethanolamine, wherein the phospholipid contains 96% -98% of phosphatidylcholine; the content of the phosphatidylethanolamine in the compound oil solution preparation is less than or equal to 0.245% (w/w);
The dexamethasone or ester thereof is selected from dexamethasone, dexamethasone palmitate, dexamethasone acetate, dexamethasone isonicotinate or dexamethasone dipropionate;
The ropivacaine or salt thereof is selected from ropivacaine hydrochloride or ropivacaine mesylate;
the ethanol is absolute ethanol, and the dosage of the absolute ethanol is 5.0-20.0% (w/w);
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 cotton seed oil, and the dosage of the oil for injection is 33.0-43.0% (w/w).
2. The formulation of claim 1, wherein the phospholipid is present in an amount of 45.0 to 50.0%.
3. The formulation of claim 1, wherein the phospholipid is present in an amount of 46.0%.
4. The formulation according to claim 1, wherein the phospholipid is selected from high purity or refined egg yolk lecithin.
5. The formulation of any one of claims 1 to 4, further comprising a pharmaceutically acceptable excipient comprising an antioxidant.
6. The formulation of claim 5, wherein the antioxidant is used in an amount of 0.02 to 1% (w/w).
7. The formulation of claim 5, wherein the antioxidant is selected from the group consisting of tocopherol, ascorbyl palmitate, dibutylphenol, t-butyl p-hydroxyanisole, cysteine, or cysteine hydrochloride, or one or more thereof.
8. The formulation of claim 5, consisting of
Or by
Or by
Or by
9. The formulation of claim 5, wherein the formulation is administered by intramuscular injection, by painting.
10. The formulation of claim 1, wherein the formulation comprises: the concentration of ropivacaine or salt thereof is 3.0-5.0% calculated by ropivacaine.
11. The formulation of claim 10, wherein the formulation comprises: the ropivacaine or salt thereof has a concentration of 4.0% based on ropivacaine.
12. The formulation of claim 1, wherein the formulation comprises: the concentration of dexamethasone or its ester is 0.01-0.3% calculated by dexamethasone.
13. The formulation of claim 12, wherein the formulation comprises: the concentration of dexamethasone or ester thereof is 0.03-0.1% based on dexamethasone.
14. The formulation of claim 1, wherein the dexamethasone or ester thereof is dexamethasone palmitate.
15. The formulation of claim 1, wherein the ropivacaine or salt thereof is ropivacaine hydrochloride.
16. The formulation of claim 1, wherein the absolute ethanol is present in an amount of 15.0 to 20.0%.
17. The formulation of claim 1, wherein the injectable oil is present in an amount of 34 to 35%.
18. The formulation of claim 1, wherein the injectable oil is selected from soybean oil, castor oil or medium chain triglycerides, or one or more thereof.
19. The formulation of claim 6, wherein the antioxidant is present in an amount of 0.04 to 0.1%.
20. The formulation of claim 19, wherein the antioxidant is present in an amount of 0.05 to 0.5%.
21. The formulation of claim 20, wherein the antioxidant is present in an amount of 0.1 to 0.5%.
22. A method of preparing the formulation of claim 1, the method comprising:
(1) Weighing components except ropivacaine or salt thereof, dexamethasone or ester thereof, placing in a closed container, heating in water bath, stirring for dissolving, and obtaining a blank oil solution;
(2) Adding ropivacaine or salt thereof, dexamethasone or ester thereof into the blank oil solution, heating in water bath, stirring and dissolving to obtain a medicinal oil solution;
(3) The medicinal oil solution is obtained by filtering, filling, nitrogen filling and sealing.
23. The method according to claim 22, wherein the method further comprises: and (3) heating in a water bath at 70 ℃ in the step (1), and heating in a water bath at 70 ℃ in the step (2).
24. The method according to claim 22, wherein the method further comprises: the drug oil solution in the step (3) is filtered by a filter membrane, wherein the filter membrane is a 0.45 μm, 0.65 μm or 0.22 μm filter membrane.
25. The preparation according to claim 1, wherein the content of phosphatidylcholine in the compound oil solution preparation is 38.0-47.86% (w/w).
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