CN111388418B - Pharmaceutical composition containing ropivacaine or pharmaceutical salt thereof - Google Patents
Pharmaceutical composition containing ropivacaine or pharmaceutical salt thereof Download PDFInfo
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- CN111388418B CN111388418B CN201811650146.5A CN201811650146A CN111388418B CN 111388418 B CN111388418 B CN 111388418B CN 201811650146 A CN201811650146 A CN 201811650146A CN 111388418 B CN111388418 B CN 111388418B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- 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
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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
- A61K47/24—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
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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
- A61K47/44—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention provides a composition containing ropivacaine or a medicinal salt thereof, which contains an active ingredient ropivacaine or a medicinal salt thereof and a solvent composition capable of dissolving the active ingredient of the medicine, wherein the solvent composition contains higher fatty acid or ester as a carrier.
Description
Technical Field
The invention relates to a long-acting pharmaceutical composition containing a local anesthetic, in particular to a pharmaceutical composition containing ropivacaine.
Background
Ropivacaine (Ropivacaine) is a novel, pure levorotatory, long-acting amide-type local anesthetic, which is a monohydrate of piperidinomethylidine hydrochloride, chemically named(s) -N-mono (2, 6-dimethylphenyl) -1-propyl-2-piperidinecarboxamide. The sensory nerve and motor nerve block separation is obvious when the concentration of the ropivacaine is low, and the toxicity of the central nervous system and the cardiovascular system is low. Is one of the substitute drugs which are lower in lipid solubility and higher in safety and are sought after the sudden cardiac arrest induced by bupivacaine reported by Albright in 1979, and is widely used for clinical anesthesia and pain treatment.
Currently, ropivacaine is used clinically by continuous administration through a jet pump type of administration device that delivers the drug into the vein, under the skin or between the dura mater and the spine. Ropivacaine is commonly used for postoperative anesthesia or analgesia, long-time continuous administration is required, and the administration mode of a jet pump type brings great inconvenience to the life of a patient. Therefore, a new ropivacaine administration form which is more convenient to use and has better treatment effect is urgently needed in clinic.
Based on clinical needs, the inventor develops a ropivacaine-containing pharmaceutical composition through intensive research, the composition can be directly applied to an incision or an affected part, and meanwhile, the composition can slowly release ropivacaine, so that the ropivacaine can be continuously released for a long time without repeated administration, the dosage form effectively improves the compliance of clinical patients, and meanwhile, the ropivacaine-containing pharmaceutical composition directly acts on the incision or the affected part, and effectively shortens the onset time of the pharmaceutical composition.
Disclosure of Invention
The invention provides a sustained-release and stable pharmaceutical composition containing ropivacaine, which can be directly applied to an incision or an affected part and is a transparent or semitransparent oily composition or an emulsion.
The invention provides a pharmaceutical composition containing ropivacaine, which contains an active ingredient ropivacaine or a pharmaceutically acceptable salt thereof and a solvent composition capable of dissolving the active ingredient of the medicine, wherein the solvent composition contains higher fatty acid or ester as a carrier, the dosage ratio (by weight ratio) of the ropivacaine or the pharmaceutically acceptable salt thereof to the higher fatty acid or ester is less than 0.167, and in certain embodiments, the dosage ratio (by weight ratio) of the ropivacaine or the pharmaceutically acceptable salt thereof to the higher fatty acid or ester is less than or equal to 0.147.
The higher fatty acid or ester according to the present invention is derived from a vegetable oil, such as castor oil, sesame oil, soybean oil, rapeseed oil, safflower oil, cottonseed oil, peanut oil, tea oil, olive oil, sunflower oil, grape seed oil, wheat germ oil, and the like, and in some embodiments the higher fatty acid or ester is castor oil or soybean oil.
The higher fatty acid or ester described herein, in some embodiments the higher fatty acid or ester refers to a mixture of oleic acid with hydroxyl group and oleic acid without hydroxyl group, in some embodiments the oleic acid with hydroxyl group accounts for more than 60% of the total weight of the higher fatty acid or ester, wherein the oleic acid with hydroxyl group accounts for more than 71.2% of the total weight of the higher fatty acid or ester, further oleic acid with hydroxyl group accounts for more than 75.4% of the total weight of the higher fatty acid or ester, in some embodiments the oleic acid with hydroxyl group accounts for more than 79.5% of the total weight of the higher fatty acid or ester, in other embodiments the oleic acid with hydroxyl group accounts for more than 80.5% of the total weight of the higher fatty acid or ester, and all of the above-mentioned ranges include the above values, wherein the oleic acid with hydroxyl group such as ricinoleic acid, and the oleic acid without hydroxyl group such as oleic acid, linoleic acid, and the like.
In some embodiments, ropivacaine or a pharmaceutically acceptable salt thereof according to the present invention is present in a weight ratio of greater than or equal to 1.0%, in some embodiments greater than or equal to 1.57%, in some embodiments greater than or equal to 2.15%, in some embodiments less than or equal to 10.0%, in other embodiments less than or equal to 8.0%, and in some embodiments less than or equal to 7.0%.
At present, the active ingredient in the clinical medication of ropivacaine is mainly ropivacaine hydrochloride, the invention unexpectedly discovers in research and development that the solubility of ropivacaine in the composition is higher, the preparation of the invention is more facilitated, and the pharmaceutical composition with high drug content is obtained.
In certain embodiments, the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 3.1mg/g, in certain embodiments the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 3.6mg/g, in other embodiments the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 5.3mg/g, further, in certain embodiments the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 6.3mg/g, in certain embodiments the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 13.1mg/g, in certain embodiments the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 15.5mg/g, and the solubility of ropivacaine or a pharmaceutically acceptable salt thereof is greater than or equal to 20 mg/g. The solvent composition of the ropivacaine-containing pharmaceutical composition of the present invention may further contain a phospholipid in an amount of 0 to 39.22 wt%, and when the phospholipid is used, the amount of the phospholipid is less than the amount of the higher fatty acid or ester.
The phospholipid of the present invention contains Phosphatidylcholine (PC) and Phosphatidylglycerol (PG), and the phospholipid may be a pharmaceutically acceptable salt such as sodium salt, potassium salt, or ammonium salt, and the phospholipid may be egg yolk lecithin, soybean lecithin, or lecithin obtained by synthesis or semi-synthesis by a known method, among which egg yolk lecithin and purified egg yolk lecithin having a high phospholipid content are preferable.
In certain embodiments, the phospholipids of the present invention comprise Phosphatidylcholine (PC) in an amount of greater than or equal to 71.2%, in further certain embodiments, greater than or equal to 75.4%, in other embodiments, greater than or equal to 80.2%, in certain embodiments, greater than or equal to 10.6%, in certain embodiments, greater than or equal to 11.4%, and in further certain embodiments, greater than or equal to 12.5%.
In the ropivacaine-containing pharmaceutical composition of the present invention, the solvent composition may further contain an organic solvent, and the further solvent used is an alcohol solvent, such as methanol, ethanol, propanol, propylene glycol, etc., in some embodiments, the solvent used is methanol, and in some embodiments, the solvent used is ethanol.
In certain embodiments, the organic solvent is present in the composition in an amount less than or equal to 20%, in certain embodiments less than or equal to 18%, in other embodiments less than or equal to 16%, and further, in certain embodiments less than or equal to 14.76% by weight.
In some embodiments of the present invention, the ropivacaine-containing pharmaceutical composition comprises a pharmaceutically active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutically active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier, and the ratio (by weight) of the amount of ropivacaine or a pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than 0.167.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises ropivacaine or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient, and a solvent composition capable of dissolving the pharmaceutically active ingredient, wherein the solvent composition comprises a higher fatty acid or ester and an organic solvent as a carrier, wherein the amount ratio (by weight ratio) of the ropivacaine or the pharmaceutically acceptable salt thereof to the higher fatty acid or ester is less than 0.167.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises ropivacaine or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient, and a solvent composition capable of dissolving the pharmaceutically active ingredient, wherein the solvent composition comprises a higher fatty acid or ester and a phospholipid as a carrier, and the ratio (by weight) of the amount of ropivacaine or a pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than 0.167.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises a pharmaceutical active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier, an organic solvent, and a phospholipid, and the ratio (by weight) of the amount of ropivacaine or a pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than or equal to 0.167.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises a pharmaceutical active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier, wherein the ratio (by weight) of the amount of ropivacaine or a pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than or equal to 0.147.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises a pharmaceutical active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier and an organic solvent, wherein the amount ratio (by weight ratio) of the ropivacaine or the pharmaceutically acceptable salt thereof to the higher fatty acid or ester is less than or equal to 0.147.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises a pharmaceutical active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester and a phospholipid as a carrier, wherein the ratio (by weight) of the amount of ropivacaine or the pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than or equal to 0.147.
In some embodiments of the present invention, the pharmaceutical composition containing ropivacaine comprises a pharmaceutical active ingredient ropivacaine or a pharmaceutically acceptable salt thereof, and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier, an organic solvent, and a phospholipid, and the ratio (by weight) of the amount of ropivacaine or a pharmaceutically acceptable salt thereof to the amount of the higher fatty acid or ester is less than or equal to 0.147.
In some embodiments, the pharmaceutical composition containing ropivacaine comprises ropivacaine as a pharmaceutical active ingredient and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier and a phospholipid, wherein the content of the higher fatty acid or ester is higher than that of the phospholipid.
In some embodiments, the pharmaceutical composition containing ropivacaine comprises an active ingredient ropivacaine and a solvent composition capable of dissolving the active ingredient, wherein the solvent composition comprises a higher fatty acid or ester and a phospholipid as a carrier, wherein the content of the higher fatty acid or ester is higher than that of the phospholipid, and the ratio (by weight) of the amount of ropivacaine to the amount of the higher fatty acid or ester is less than or equal to 0.167.
In some embodiments, the pharmaceutical composition containing ropivacaine comprises the active ingredient ropivacaine and a solvent composition capable of dissolving the pharmaceutical active ingredient, wherein the solvent composition comprises a higher fatty acid or ester as a carrier and a phospholipid, wherein the content of the higher fatty acid or ester is higher than that of the phospholipid, and the ratio (by weight) of the amount of the ropivacaine to the amount of the higher fatty acid or ester is less than or equal to 0.147.
The ropivacaine-containing pharmaceutical composition according to the present invention may, in some embodiments, contain an antioxidant, such as cysteine and its hydrochloride, tocopherol, ascorbic acid (Vc), etc., wherein the tocopherol may be alpha-tocopherol, beta-tocopherol, ϒ -tocopherol, or delta-tocopherol.
The ropivacaine-containing pharmaceutical composition of the present invention is in the form of an emulsion or a transparent, translucent oily liquid, which can be directly injected or applied to the inside and outside of an incision or wound.
The ropivacaine-containing pharmaceutical composition improves the problems of poor solubility and low drug content of ropivacaine salt serving as a pharmaceutical active ingredient, can directly act on an affected part, greatly reduces the drug action time, and finally has higher drug content, obviously improved sustained release performance, greatly reduced drug use times of a patient and improved compliance of the patient.
Drawings
FIG. 1 Release Profile for each formulation of example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1 determination of solubility of ropivacaine and ropivacaine hydrochloride
Ropivacaine and ropivacaine hydrochloride are weighed according to the prescription amount, dissolved in a corresponding mixed solvent, subjected to ultrasonic treatment, shaken in a water bath at 25 ℃ overnight, taken out, centrifuged, and the supernatant is taken out, and subjected to HPLC (high performance liquid chromatography) to determine the content, wherein the experimental parameters and the obtained results are shown in Table 1 as follows:
TABLE 1 determination of ropivacaine and ropivacaine solubility
From the above results, it is understood that the solubility of the pharmaceutically active ingredient differs among the solvent compositions, and further, in the sample prescription screening, the solubility of the pharmaceutically active ingredient is preferably more than 13.1mg/g, more preferably more than 15.5mg/g, and still more preferably more than 20 mg/g; since the phospholipid cannot be dissolved and the sample cannot be prepared when the solvent composition does not contain a carrier and contains a phospholipid or ethanol, the solvent composition needs to contain a carrier component to develop the sample when the phospholipid is contained in the solvent composition, the solubility of ropivacaine is higher than that of ropivacaine hydrochloride (for example, No. 6 and No. 9) when the components and the content in the solvent composition are the same, and ropivacaine is preferable as a pharmaceutically active component in the formulation screening.
TABLE 2 determination of phospholipid and Castor oil fractions in solvent composition
Example 2
The prescription of the composition is as follows:
the preparation method comprises the following steps:
1) weighing the auxiliary materials of each formula in a 10ml penicillin bottle, immediately sealing and dissolving at 60 ℃;
2) weighing API according to the prescription, putting a stirrer, and stirring and dissolving at 60 ℃;
3) filtering each prescription with 0.8umPES membrane to obtain a sample;
determination of content
The content of the sample was measured, and the measurement results are shown in table 3:
TABLE 3 results of measurement of contents
Determination of the degree of Release
The release study was carried out using PBS (pH 7.4) as the release medium, and the formulation solution containing 0.02g of the pharmaceutically active ingredient was added to a dialysis bag (MD 25-14, molecular weight cut-off 14000) and the release was measured by sampling at 35 ℃ and 50rpm for 1h, 3h, 6h, 18h, 24h, 48h, 72h and 96h, respectively, and the results are shown in Table 4:
TABLE 4 measurement results of Release degree
From the above results of the release rate, the prescription 6 releases the fastest, the prescription 1 releases the fastest, the prescription 2 and the prescription 3 release the slowest, and the prescription 4 and the prescription 5 are centered, and it is known to those skilled in the art that the release rate is too fast to achieve the effect of sustained release, and the release rate is too slow to prolong the onset time of the drug, so that the drug cannot achieve good therapeutic effect. The use of higher amounts of lecithin than the oil in formulations 2 and 3 resulted in a decrease in the release rate of the drug, prolonging the onset of action of the drug, and an excessively fast release rate when the composition contained only solvent and ropivacaine.
Example 3
Composition prescription 1 group
The preparation method comprises the following steps:
1) weighing the auxiliary materials in the formulas 7 and 8, adding the auxiliary materials into a 20ml penicillin bottle, adding a stirrer, and stirring in a water bath at 60 ℃ to dissolve;
weighing 10 ropivacaine and auxiliary materials according to the formula, adding the ropivacaine and the auxiliary materials into a 20ml penicillin bottle, adding a stirrer, and stirring and dissolving in a water bath at 60 ℃;
2) dissolving the auxiliary materials of the formulas 7, 8 and 9 until the auxiliary materials are transparent, cooling to room temperature, opening a cover, adding ropivacaine, rolling the cover to seal, and stirring in a water bath at 60 ℃ to dissolve;
3) after the temperature of each prescription is reduced to room temperature, 0.8um PES membrane is filtered and collected in a 10ml penicillin bottle to obtain samples.
Experimental phenomena: in the preparation process of the formula 8, turbidity appears after the temperature is reduced to room temperature, when the dosage of the ropivacaine is reduced to 0.22g, the dosage of other materials is inconvenient (namely the dosage is the same as that of the formula 7), and a sample is clear and does not appear turbidity after the preparation is finished.
Composition prescription 2 groups
Preparation method of formula 9:
1) weighing the prescription auxiliary materials, adding the prescription auxiliary materials into a 20ml penicillin bottle, adding a stirrer, and stirring and dissolving in water bath at 60 ℃;
2) dissolving the auxiliary materials in the prescription to be transparent, cooling to room temperature, opening a cover, adding ropivacaine, rolling the cover to seal, and stirring in a water bath at 60 ℃ to dissolve;
3) after the formula 9 is cooled to room temperature, 0.8um PES membrane is filtered and collected in a 10ml penicillin bottle to obtain a sample.
The preparation method of the formula 10 comprises the following steps:
1) weighing 10 ropivacaine and auxiliary materials according to a prescription, adding the ropivacaine and the auxiliary materials into a 20ml penicillin bottle, adding a stirrer, and stirring and dissolving in a water bath at 60 ℃;
2) after the formula 9 is cooled to room temperature, 0.8um PES membrane is filtered and collected in a 10ml penicillin bottle to obtain a sample.
The experimental phenomenon is as follows: clear samples were obtained for both recipe 9 and recipe 10.
Composition formula 3 groups
Preparation methods of formulas 11 and 12: the preparation method is the same as the preparation method of the formula 9.
Composition formula 4 groups
Preparation method of formula 13: the preparation method is the same as the preparation method of the formula 10.
From the above experimental results, it can be seen that the difference between the formula 7 and the formula 8 is that the amount of ropivacaine used is different, the amount of ropivacaine in the formula 8 is increased, which results in turbidity of the prepared formulation after cooling, the formula 9 increases the amount of ropivacaine and castor oil, which reduces the amount of lecithin, the formula 10 is the same as the amount of ropivacaine in the formula 9, the auxiliary lecithin is removed from the formula 10, and castor oil is added, which results show that the stability of the prepared solvent is increased along with the increase of the amount of ropivacaine, when the amount ratio (weight ratio) of ropivacaine to castor oil is greater than or equal to 0.167 (formula 8), the obtained ropivacaine composition cannot exist stably, and when the amount ratio (weight ratio) of ropivacaine to castor oil is less than 0.167, the stable ropivacaine composition can be obtained, further, when the amount ratio (weight ratio) of ropivacaine to castor oil is not more than 0.147 (formula 7), a stable ropivacaine composition can be obtained.
1. Animal experiments
(1) And (3) test article information:
(2) reagent information
(3) Device information
(4) Information on laboratory animals
SD rat, male, SPF grade, 200-; beijing Jinmuyang laboratory animal Breeding Limited liability company, laboratory animal quality certification: no: 11401300086894, respectively; license number: SCXK (Jing) 2014-.
(5) Experimental procedure
The times of the contraction reaction of the punctured mouse are examined, the medicine is smeared on the punctured part of the mouse, the smaller the times of the contraction reaction, the better the analgesic effect of the preparation is shown, the results are shown in table 5,
TABLE 5 animal experiment results of prescriptions 7, 9 and 10, 11, 12, 13
From the above results, it can be seen that the effect of the prescription 10 is the best, the ropivacaine contents of the prescription 9 and the prescription 10 are the same, and the dosages of the adjuvants are different, so that the dosages of the adjuvants in the prescription of the preparation have an important influence on the drug effect, the prescription 11 is basically ineffective, and compared with the prescription 12, the ropivacaine content is different, further showing that the pharmaceutically active ingredient has an important influence on the curative effect of the preparation, the dosages of the ropivacaine in the invention should be more than 1%, and further the content of the ropivacaine is more than 1.97%.
Example 4
Composition prescription
Preparation methods of formulas 14 and 15:
1) weighing the auxiliary materials according to the prescription amount, and stirring and dissolving for 20min in water bath at 60 ℃;
2) weighing ropivacaine according to the prescription amount, correspondingly adding the ropivacaine into the auxiliary material solution, and stirring and dissolving at room temperature;
3) filtering with 0.8um PES filter membrane, and packaging in 10ml penicillin bottles, wherein each penicillin bottle has 5 bottles per bottle and 10 g;
4) and (5) filling nitrogen, and then sealing by rolling a cover.
Preparation method of formula 16
1) Weighing the auxiliary materials and ropivacaine according to the prescription amount, and stirring at room temperature for dissolving;
2) filtering with 0.8um PES filter membrane, and packaging in 10ml penicillin bottles, wherein each penicillin bottle has 5 bottles per bottle and 10 g;
3) and (5) filling nitrogen, and then sealing by rolling a cover.
1. Stability test
The test instrument:
and (3) stability test:
accelerated and long-term experiments were conducted on recipes 14-16 to investigate the stability of each recipe.
Accelerated testing: placing the three prescriptions in an incubator at 40 deg.C, sampling at 0 hr, 1 month, 2 months, and 3 months, respectively, and detecting their contents by HPLC;
and (3) long-term experiment: placing the three prescriptions in an incubator at 25 deg.C, sampling at 0 hr, 1 month, 2 months, and 3 months, respectively, and detecting their contents by HPLC;
TABLE 6 stabilization of the New test results
As can be seen from the results, the ropivacaine-containing compositions having high stability were obtained in all of the formulations 14 to 15.
2. Animal experiments
(1) And (3) test article information:
(2) reagent information
(3) Device information
(4) Information on laboratory animals
SD rat, male, SPF grade, 200-; beijing Jinmuyang laboratory animal Breeding, Limited liability company. Quality certification of experimental animals: no: 11401300086894; license number: SCXK (Jing) 2014-.
(5) Experimental procedure
5.1 animal feeding
The temperature of the breeding room is 22 +/-3 ℃, the humidity is 40-70%, and the light and the shade alternate in 12 hours;
feed: rat maintenance material (ao synergetics);
animals had free access to food and water.
5.2 test procedure
1) Randomly grouping 10 in each group before the operation one day;
2) anesthetizing animals with isoflurane, disinfecting the right hind paw of a rat, making a longitudinal incision with the length of about 1.0cm from the beginning of 0.5cm at the near end of the sole to the toe part by using a scalpel according to a Brennan method, cutting the skin, then picking up the muscles under the paw by using ophthalmological forceps or hemostatic forceps, longitudinally cutting the incision from left to right to ensure the integrity of the start-stop attachment points of the muscles, and pressing and suturing the hemostatic forceps by using a fine line;
3) injecting a sample from the wound suture position by using a 1ml injector after suturing until a small amount of medicine overflows from the wound suture position, and weighing the injector before and after administration to calculate the actual administration amount by using a weight reduction method;
4) after administration, 3.5h, the rat is placed in a detection cage to adapt to the environment for 20min, the middle part of the plantar of the hind limb to be detected is slowly and softly stimulated by a probe of a pain instrument after the rat is not in a looking state and in a resting state, if the rat generates a rapid foot contraction reaction due to stimulation, the reading (g) of the foot contraction reaction is recorded, and the foot contraction reaction generated due to the body movement of the rat is not counted. Eight repeated measurements were made and the results recorded, with the mean being the pain threshold of the animal.
5.3 data processing and statistical analysis method:
independent samples using Excel 2010tThe examination compares the lifting foot tolerance of each group of animals with the model group,pa significant difference was found to be < 0.05.
5.4 Experimental results:
TABLE 7 results of animal experiments
As can be seen from the results, the pain threshold of the animals in groups 2 and 3 is significantly increased compared with that in the model control group, while the pain threshold of the animals in group 1 is not significantly different compared with that in the model control group. In addition, the pain thresholds were also significantly increased in group 2 and group 3 animals compared to group 1: (p< 0.001), i.e. group 1 was completely ineffective, while groups 2 and 3 had significant analgesic effects.
Claims (6)
1. A composition containing ropivacaine or its medicinal salt comprises ropivacaine or its pharmaceutically acceptable salt, ethanol, phospholipid and higher fatty acid or ester as medicinal carrier;
wherein the content of ropivacaine or pharmaceutically acceptable salt thereof as a medicinal active ingredient is more than or equal to 1.57 percent, and the content of phospholipid in the composition is 0 to 39.22 percent;
wherein the dosage ratio of the active pharmaceutical ingredient to the higher fatty acid or ester is less than 0.167;
the hydroxy oleic acid in the composition accounts for more than 71.2 percent of the total amount of the higher fatty acid or ester;
the content of phospholipids in the composition is less than the content of higher fatty acids or esters;
wherein the higher fatty acid or ester is castor oil or soybean oil.
2. The composition of claim 1, wherein the ratio of the amount of the pharmaceutically active ingredient to the amount of the higher fatty acid or ester is less than or equal to 0.147.
3. A composition containing ropivacaine or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, characterised in that the active ingredient of the composition is ropivacaine.
4. A composition containing ropivacaine or a pharmaceutically acceptable salt thereof according to claim 1 characterised in that the higher fatty acid or ester in the composition is a mixture of oleic acid with and without oleic acid with hydroxyl groups.
5. A composition according to claim 1 comprising ropivacaine or a pharmaceutically acceptable salt thereof wherein the solubility of the composition ropivacaine or a pharmaceutically acceptable salt thereof is greater than 13.1 mg/g.
6. A composition according to claim 1 comprising ropivacaine or a pharmaceutically acceptable salt thereof wherein the phospholipid content of the composition is greater than or equal to 71.2% and the phospholipid content of the phospholipid is greater than or equal to 10.6%.
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| 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 |
| CN108354903A (en) * | 2018-04-11 | 2018-08-03 | 西安力邦生物医药技术有限公司 | A kind of regional anesthesia analgesia sustained release drug delivery systems and its preparation method and application |
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| US20070196452A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Flux-enabling compositions and methods for dermal delivery of drugs |
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| 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 |
| CN103142458A (en) * | 2013-01-22 | 2013-06-12 | 莱普德制药有限公司 | Component and preparation method of non-addition analgesia slow release medicine delivering system |
| CN108354903A (en) * | 2018-04-11 | 2018-08-03 | 西安力邦生物医药技术有限公司 | A kind of regional anesthesia analgesia sustained release drug delivery systems and its preparation method and application |
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