A pharmaceutical composition comprising a local anesthetic and fospropofol disodium, its preparation method and use, and a combined drug

Abstract

The present invention provides a pharmaceutical composition comprising a local anesthetic and fospropofol disodium, a preparation method and use thereof, and a combination drug, belonging to the field of pharmaceutical preparations. The pharmaceutical composition and the combination drug have both analgesic and sedative effects. Through the additive or synergistic effect between the drugs, the onset time of fospropofol disodium can be shortened, the pharmacodynamic effect can be enhanced, the drug dosage can be reduced, the pH value of the fospropofol disodium solution can be improved, adverse reactions during anesthesia induction can be alleviated, the number of medications required by anesthesiologists can be reduced, and the anesthesia induction process can be made more convenient, thereby achieving a more ideal anesthetic effect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition comprising a local anesthetic and fospropofol disodium, a preparation method and use thereof, and a combined drug. Background Art

[0002] General anesthesia is widely used to alleviate both physical and psychological pain during surgery. During general anesthesia, loss of consciousness (sedation), pain relief (analgesia), and avoidance of physical activity (muscle relaxation) are essential to achieve satisfactory surgical conditions. General anesthesia is divided into three phases: induction, maintenance, and recovery. Fospropofol disodium for injection is a new, water-soluble intravenous anesthetic. It is a propofol prodrug and a Class 1.1 new drug. After entering the body, fospropofol disodium is converted to propofol by alkaline phosphatase in the liver and vascular endothelial cells. After crossing the blood-brain barrier, propofol binds to the 11th subunit of the gamma-aminobutyric acid A (GABAA) receptor, increasing chloride influx and producing hyperpolarization, which inhibits postsynaptic neurons. It also inhibits the excitability of aspartate and glutamate receptors, reducing calcium ion entry into the cell, inhibiting postsynaptic neurons and producing a sedative effect. Compared to propofol, fospropofol disodium offers the following advantages: Due to its excellent water solubility, it does not require the fat emulsion carrier used in commercial propofol formulations. It also has milder respiratory and circulatory suppression and lower injection pain compared to propofol. However, fospropofol disodium has a relatively slow onset of action, and loss of consciousness after administration is prolonged. Based on previous studies and clinical experience, loss of consciousness occurs in approximately 2-3 minutes after administration of fospropofol disodium at a dose of 12 mg / kg, and in approximately 3-4 minutes after administration of fospropofol disodium at a dose of 10 mg / kg. Furthermore, fospropofol disodium is a sedative and has no significant analgesic effect. Furthermore, due to the presence of a phosphate group, it may dissociate in vivo, potentially causing unusual sensations such as itching during anesthesia induction. Itch is an unpleasant, multifaceted, and complex sensation or reaction that significantly impacts patient comfort during anesthesia induction. Previous studies and early clinical experience have shown that the incidence of paresthesia caused by fospropofol disodium is approximately 62%, with pruritus being particularly prominent. This adverse reaction has impacted the clinical application of fospropofol disodium.

[0003] Lidocaine is a medium-acting amide local anesthetic and a sodium channel blocker. It can be used not only for local anesthesia but also for systemic administration to reduce patient stress responses. Studies have demonstrated the efficacy and safety of intravenous lidocaine in improving perioperative pain. A meta-analysis showed that perioperative lidocaine (doses of 5-10 mg, 20-30 mg, ≥40 mg) mixed with propofol for anesthesia induction was safe and effective in improving propofol-induced injection pain. Compared with the control group, the use of a lidocaine-propofol mixture for induction reduced the risk of propofol-induced injection pain by 60%. However, the effectiveness of lidocaine against paresthesia caused by fospropofol disodium remains unclear. Summary of the Invention

[0004] The object of the present invention is to provide a pharmaceutical composition comprising a local anesthetic (such as lidocaine or a salt thereof) and fospropofol disodium, to address the deficiencies of existing drugs, shorten the onset time of fospropofol disodium, compensate for the lack of analgesic effect of fospropofol disodium, improve the pH of the fospropofol disodium drug solution to make it closer to the physiological pH of the human body, and improve paresthesia such as itching caused by fospropofol disodium, reduce the incidence of adverse reactions, and make anesthesia induction smoother and more convenient.

[0005] The present invention provides a pharmaceutical composition comprising a local anesthetic and fospropofol disodium.

[0006] Furthermore, the local anesthetic is selected from amide local anesthetics or ester local anesthetics.

[0007] Furthermore, the amide local anesthetic or ester local anesthetic is selected from one or more of lidocaine or its salt, ropivacaine or its salt, bupivacaine or its salt, levobupivacaine or its salt, procaine or its salt, tetracaine or its salt, chloroprocaine or its salt, etidocaine or its salt, prilocaine or its salt, and mepivacaine or its salt.

[0008] Furthermore, the salt is hydrochloride, sulfate, bromate, citrate, succinate, maleate, glycolate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, levulinate, gluconate, glucuronate, lactate, malate, pyruvate, fumarate, tartrate, sulfonate, tricarboxylate, malonate, adipate, glutarate, itaconate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydroxypropionate, ascorbate, aspartate or glutamate.

[0009] Furthermore, the salt is hydrochloride, sulfate, tartrate, maleate or citrate.

[0010] Furthermore, the mass ratio of the local anesthetic to fospropofol disodium is (1-10):50.

[0011] Furthermore, the mass ratio of the local anesthetic to fospropofol disodium is (5-7.5):50.

[0012] Furthermore, the preparation is prepared with local anesthetic and fospropofol disodium as active ingredients and a pharmaceutically acceptable carrier.

[0013] Furthermore, the preparation is a tablet, capsule, powder, pill, granule, injection or emulsion.

[0014] Furthermore, the preparation is an injection, wherein the concentration of fospropofol disodium is 45-55 mg / mL.

[0015] Furthermore, in the injection, the concentration of fospropofol disodium is 50 mg / mL.

[0016] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: uniformly mixing the local anesthetic and fospropofol disodium to obtain the pharmaceutical composition; or dissolving the local anesthetic and fospropofol disodium in an aqueous solution to obtain the pharmaceutical composition.

[0017] The present invention also provides use of the pharmaceutical composition in preparing a drug with sedative and / or analgesic effects.

[0018] The pharmaceutical composition of the present invention may also contain auxiliary substances, stabilizers, wetting agents and other commonly used additives, such as sodium chloride, glucose, lactose, citric acid, tartaric acid, magnesium stearate, gypsum powder, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, ascorbic acid, mannitol, etc.

[0019] The pharmaceutical composition of the present invention can be prepared according to conventional preparation processes of various preparations.

[0020] When the pharmaceutical composition of the present invention is in the form of an injection, the aqueous solution used for dissolution can be 0.9% sodium chloride injection.

[0021] The present invention also provides a combined drug with sedative and / or analgesic effects, which contains a local anesthetic and fospropofol disodium in unit preparations of the same or different specifications for simultaneous or separate administration, and a pharmaceutically acceptable carrier.

[0022] Furthermore, the local anesthetic is selected from amide local anesthetics or ester local anesthetics.

[0023] Furthermore, the amide local anesthetic or ester local anesthetic is selected from one or more of lidocaine or its salt, ropivacaine or its salt, bupivacaine or its salt, levobupivacaine or its salt, procaine or its salt, tetracaine or its salt, chloroprocaine or its salt, etidocaine or its salt, prilocaine or its salt, and mepivacaine or its salt.

[0024] Furthermore, the salt is hydrochloride, sulfate, bromate, citrate, succinate, maleate, glycolate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, levulinate, gluconate, glucuronate, lactate, malate, pyruvate, fumarate, tartrate, sulfonate, tricarboxylate, malonate, adipate, glutarate, itaconate, glycerate, methacrylate, isocrotonate, β-hydroxybutyrate, crotonate, angelate, hydroxypropionate, ascorbate, aspartate or glutamate.

[0025] Furthermore, the salt is hydrochloride, sulfate, tartrate, maleate or citrate.

[0026] Furthermore, the mass ratio of the local anesthetic to fospropofol disodium is (1-10):50.

[0027] Furthermore, the mass ratio of the local anesthetic to fospropofol disodium is (5-7.5):50.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention provides a pharmaceutical composition comprising a local anesthetic and fospropofol disodium. The pharmaceutical composition can shorten the induction time, enhance the analgesic effect, and improve the pH value of the drug solution. The active ingredient of the pharmaceutical composition remains stable after a long storage period without the presence of foreign matter or crystallization. Moreover, even after long-term storage, the release of the active ingredient remains reproducibly unchanged and independent.

[0030] The pharmaceutical composition provided by the present invention can be directly used clinically, including for anesthesia induction. The pharmaceutical composition has both analgesic and sedative effects. Through the additive or synergistic effects of the drugs, the onset time of fospropofol disodium can be shortened, the pharmacodynamic effects can be enhanced, the drug dosage can be reduced, the pH of the fospropofol disodium solution can be improved, adverse reactions during anesthesia induction can be alleviated, the number of medications required by anesthesiologists can be reduced, and the anesthesia induction process can be made more convenient, thereby achieving a more ideal anesthetic effect.

[0031] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0032] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 : The pH change test results of each group of drug solutions in Experimental Example 1 with the preparation time.

[0034] Figure 2 : The results of the effects of each group of drugs on the sedative effect of rats in Experimental Example 2. In the figure, ****P<0.0001, ***P<0.001, **P<0.01.

[0035] Figure 3 : Respiratory rate of rats in each group before and after administration in Experimental Example 2.

[0036] Figure 4 : Standard curve of fospropofol disodium.

[0037] Figure 5 : Changes in the plasma concentration of fospropofol disodium in each group of rats in Experimental Example 3 with administration time.

[0038] Figure 6 : Drug-time curve of fospropofol disodium in group A of Experimental Example 3.

[0039] Figure 7 : Drug-time curve of fospropofol disodium in group B in Experimental Example 3.

[0040] Figure 8 : Drug-time curve of fospropofol disodium in group C of Experimental Example 3. DETAILED DESCRIPTION

[0041] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0042] Fospropofol disodium is produced by Yichang Renfu Pharmaceutical Co., Ltd.; lidocaine hydrochloride injection (national medicine standard number H14024045) is produced by Shanxi Yuncheng Shijiao Yinhu Pharmaceutical Co., Ltd.; lidocaine hydrochloride standard (CAS: 6108-05-0) is produced by Tanmo Quality Inspection-Standard Material Center.

[0043] Example 1: Preparation of a pharmaceutical composition injection containing lidocaine hydrochloride and fospropofol disodium

[0044] A pharmaceutical composition injection containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium was prepared according to the following formula:

[0045] Fospropofol disodium 100mg,

[0046] 2% lidocaine hydrochloride injection 0.5ml,

[0047] Dilute to 2 ml with 0.9% saline.

[0048] Example 2: Preparation of a pharmaceutical composition injection containing lidocaine hydrochloride and fospropofol disodium

[0049] A pharmaceutical composition injection containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium was prepared according to the following formula:

[0050] Fospropofol disodium 100mg,

[0051] 2% lidocaine hydrochloride injection 0.75ml,

[0052] Dilute to 2 ml with 0.9% saline.

[0053] The following is the preparation method of the control sample.

[0054] Comparative Example 1: Preparation of Lidocaine Hydrochloride Injection

[0055] Prepare 5 mg / ml lidocaine hydrochloride injection according to the following formula:

[0056] 2% lidocaine hydrochloride injection 0.5ml,

[0057] Dilute to 2 ml with 0.9% saline.

[0058] Comparative Example 2: Preparation of Lidocaine Hydrochloride Injection

[0059] Prepare 7.5 mg / ml lidocaine hydrochloride injection according to the following formula:

[0060] 2% lidocaine hydrochloride injection 0.75ml,

[0061] Dilute to 2 ml with 0.9% saline.

[0062] Comparative Example 3: Preparation of Fospropofol Disodium Injection

[0063] Prepare 50 mg / ml fospropofol disodium injection according to the following formula:

[0064] Fospropofol disodium 100mg,

[0065] Dilute to 2 ml with 0.9% saline.

[0066] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0067] Experimental Example 1: Stability Test

[0068] 1. Experimental Methods

[0069] The injections prepared in Examples 1-2 and Comparative Examples 1-3 were subjected to a light inspection test and a pH test (3 mice in each group, a total of 5 groups: Group A 5 mg / ml lidocaine hydrochloride injection, Group B 7.5 mg / ml lidocaine hydrochloride injection, Group C 50 mg / ml fospropofol disodium injection, Group D a pharmaceutical composition injection containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium; Group E a pharmaceutical composition injection containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium). The testing time points were immediately after preparation, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 4 d, 5 d, 6 d, 7 d, and 14 d.

[0070] 2. Experimental Results

[0071] 2.1 Light inspection test

[0072] When each sample in each group was inspected by light immediately after drug preparation (i.e., 0h), 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 4d, 5d, 6d, 7d, and 14d, no crystallization or precipitation was observed, and all samples were colorless and transparent solutions.

[0073] 2.2 pH change detection

[0074] Table 1. pH change test results of each group of drug solutions with preparation time

[0075]

[0076] The results are shown in Table 1 and Figure 1 As shown in the figure, it can be seen that the pH values ​​of Group A and Group B solutions increased with the extension of preparation time; the pH value of Group C solution decreased with the extension of preparation time; and the pH values ​​of Group C and Group D solutions remained basically stable with the extension of preparation time, and the pH values ​​were closer to the physiological pH of the human body (pH=7.35-7.45).

[0077] The above experimental results show that the pharmaceutical composition injection containing lidocaine hydrochloride and fospropofol disodium of the present invention has excellent storage stability, and the pharmaceutical composition injection can improve the pH of the fospropofol disodium drug solution to make it closer to the physiological pH of the human body.

[0078] Experimental Example 2: Pharmacodynamic Study

[0079] This experiment is to study the effects of the drug composition injection on analgesia, sedation and improvement of adverse reactions such as itching. The experimental results are as follows:

[0080] 1. Materials

[0081] Experimental drugs:

[0082] 50 mg / ml fospropofol disodium injection (prepared in Comparative Example 3);

[0083] a pharmaceutical composition injection containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (prepared in Example 1);

[0084] A pharmaceutical composition injection containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (prepared in Example 2).

[0085] Experimental animals: SD rats, male, weighing 280-300 g, were provided by Chengdu Dashuo Experimental Animal Co., Ltd.

[0086] Rearing conditions: room temperature 20-25°C, relative humidity 38%-41%, artificial lighting, 12h light and dark, solid feed and tap water, free access to food and water, good ventilation.

[0087] 2. Experimental Methods

[0088] Thirty-six SD rats were randomly divided into three groups (n=12):

[0089] Group A: 50 mg / ml fospropofol disodium injection (dosage based on fospropofol disodium: 82 mg / kg, iv);

[0090] Group B: administered with an injection of a pharmaceutical composition containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (dosage based on fospropofol disodium: 82 mg / kg, iv);

[0091] Group C: administered with an injection of a pharmaceutical composition containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (administered dose based on fospropofol disodium: 82 mg / kg, iv).

[0092] 2.1 Evaluation of sedative and analgesic effects

[0093] Sedation was assessed using the righting reflex assessment scale (1 = complete loss of righting reflex; 2 = uncoordinated movement, righting reflex not restored within 30 seconds; 3 = uncoordinated movement, righting reflex restored within 30 seconds; 4 = coordinated movement, righting reflex restored within 10 seconds; 5 = fully awake). Analgesia was assessed using the pinch reflex score (0 = no response to pinch, 1 = response to pinch). Before administration, the rats' basal righting reflex score and pinch reflex were assessed; after administration, the rats' righting reflex was assessed: the time for the righting reflex to disappear (righting reflex score = 1 point) was assessed, the time from the end of injection to the disappearance of the righting reflex was defined as the sedation latency, the time from the disappearance of the righting reflex to the recovery of the righting reflex (righting reflex score = 3 points) was defined as the sedation duration, and the time from the recovery of the righting reflex to the recovery of coordinated activity (righting reflex score = 4 points) was defined as the recovery period; after administration, the rats' pinch reflex was assessed: the rat's right foot was clamped firmly with hemostatic forceps, and the rat was observed for leg withdrawal reaction. No leg withdrawal indicated the disappearance of the pain response, and the incidence of no leg withdrawal was defined as the analgesia rate.

[0094] 2.2 Evaluation of the effect on improving itching

[0095] According to the above grouping and administration method, after the rats are administered, the rats are observed to see whether they have scratching behavior, and the frequency of scratching behavior from the time of administration to the time when the rats are awake is recorded.

[0096] 2.3 Evaluation of the impact on respiratory rate

[0097] The rats were grouped according to the above grouping method. The basal respiratory rate of the rats was recorded before each administration (observe the number of abdominal movements of the rats in 30 seconds). The respiratory rate of the rats was recorded in the same way 5 minutes, 10 minutes and 15 minutes after administration.

[0098] 3. Statistical Analysis Methods

[0099] The data were statistically analyzed using Graphpad Prism 8.0.2. Results are expressed as mean ± standard deviation. Comparisons of means between groups were performed using ANOVA, and pairwise comparisons were performed using the Turkey method. Analgesia rates were compared using the chi-square test. P A value <0.05 was considered statistically significant.

[0100] 4. Experimental Results

[0101] One rat in each of Group A, Group B, and Group C experienced tail vein injection failure, so there were 11 rats in Group A, 11 rats in Group B, and 11 rats in Group C for the experiment.

[0102] 4.1 Sedative Effect

[0103] Table 2. Average time of sedation latency, sedation duration, and recovery period of rats in each group, as well as the results of one-way ANOVA P Value size

[0104]

[0105] Note: The results are presented as mean ± standard deviation.

[0106] The results are shown in Table 2 and Figure 2 As shown in the figure, the combined administration of 5 mg / ml or 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium significantly shortened the loss of righting reflex and prolonged the recovery of righting reflex in rats, without significantly prolonging the recovery of coordinated activity. This suggests that the combined administration of lidocaine hydrochloride and fospropofol disodium significantly shortened the onset of fospropofol disodium's effect.

[0107] 4.2 Analgesic effect

[0108] Table 3. Number of rats in each group with disappearance of pinch reflex

[0109]

[0110] Note: Compared with group A, P =0.396; compared with group A and group C, P <0.001; compared with group B and group C, P =0.003.

[0111] The experimental results are shown in Table 3. It can be seen that compared with Group A, the number of disappearances of pinch reflex in rats in Group B increased; compared with Group A and Group B, the number of disappearances of pinch reflex in rats in Group C increased significantly ( P <0.001), indicating that the combined administration of 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium can significantly compensate for the analgesic effect of fospropofol disodium.

[0112] 4.3 Incidence of pruritus

[0113] During the experiment, 5 rats in Group A, 1 rat in Group B, and 2 rats in Group C showed scratching behavior during the anesthesia recovery period. No rats in any group showed skin scratching.

[0114] The above experimental results show that the combined administration of lidocaine hydrochloride and fospropofol disodium can improve paresthesias such as itching caused by fospropofol disodium.

[0115] 4.4 Effects on respiratory rate

[0116] Table 4. Respiratory rate of rats in each group before and after administration

[0117]

[0118] The results are shown in Table 4 and Figure 3 As shown in Figure 2, there was no significant statistical difference in the respiratory rate of rats in each group at each time.

[0119] 4.5 Incidence of adverse reactions

[0120] During the sedation period, two rats in group A experienced limb convulsions, while one rat in group B and one rat in group C experienced limb convulsions. No other obvious adverse reactions were observed. This suggests that the combined administration of lidocaine hydrochloride and fospropofol disodium can significantly reduce the incidence of adverse reactions.

[0121] The above experimental results show that the combined administration of lidocaine hydrochloride and fospropofol disodium can shorten the onset time of fospropofol disodium, compensate for the lack of analgesic effect of fospropofol disodium, improve sensory abnormalities such as itching caused by fospropofol disodium, reduce the incidence of adverse reactions, and make anesthesia induction smoother and more convenient.

[0122] Experimental Example 3: In vivo pharmacokinetic evaluation

[0123] 1 Experimental materials and animals

[0124] Reagents: lidocaine hydrochloride injection, fospropofol disodium, 0.9% normal saline, heparin, acetonitrile, methanol, trifluoroacetic acid, ultrapure water.

[0125] Experimental drugs:

[0126] 50mg / ml fospropofol disodium injection;

[0127] A pharmaceutical composition injection containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium;

[0128] A pharmaceutical composition injection containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium.

[0129] Experimental instruments and equipment: Waters 2695 high performance liquid chromatograph, 2475 fluorescence spectrophotometer, electronic balance, high-speed refrigerated centrifuge.

[0130] Experimental animals: Male SD rats, weighing 280-300 g, were provided by Chengdu Dashuo Experimental Animal Co., Ltd.

[0131] Rearing conditions: room temperature 20-25°C, relative humidity 38%-41%, artificial lighting, 12h light and dark, solid feed and tap water, free access to food and water, good ventilation.

[0132] 2 Experimental methods

[0133] 2.1 Experimental Animal Grouping

[0134] Nine SD rats were randomly divided into three groups (n=3):

[0135] Group A: 50 mg / ml fospropofol disodium injection (dosage based on fospropofol disodium: 82 mg / kg, iv);

[0136] Group B: administered with an injection of a pharmaceutical composition containing 5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (dosage based on fospropofol disodium: 82 mg / kg, iv);

[0137] Group C: administered with an injection of a pharmaceutical composition containing 7.5 mg / ml lidocaine hydrochloride and 50 mg / ml fospropofol disodium (administered dose based on fospropofol disodium: 82 mg / kg, iv).

[0138] 2.2 Medication and blood collection methods

[0139] Each rat was injected with a tail vein catheter according to the above-mentioned administration method. The administration speed was completed in about 10 seconds. The time was immediately kept after the administration, and blood was collected from the tail vein at 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h after the administration.

[0140] 2.3 Venous blood processing

[0141] Blood was collected from each rat using a heparinized centrifuge tube, with a volume of approximately 0.5 ml per collection. Plasma was immediately placed on ice after collection and centrifuged within half an hour for 10 minutes at 3500 rpm at 4°C. After centrifugation, the upper plasma layer was removed and stored in a -80°C ultra-low temperature freezer.

[0142] 2.3 Plasma processing

[0143] After the plasma is thawed on ice, it is vortexed and thoroughly mixed with acetonitrile in a volume ratio of 1:3 to precipitate the protein. The plasma is then centrifuged in a low-temperature ultracentrifuge at a speed of 8000 rpm for 10 minutes at 4 degrees Celsius. The supernatant is collected after centrifugation.

[0144] 2.4 Chromatographic methods

[0145] 1) Sample Preparation: Prepare the chromatographic samples by taking the prepared supernatant according to the group. Mix the supernatant with ultrapure water in a volume ratio of 1:1. The mixed solution volume is 200 μl and set aside.

[0146] 2) Preparation of Fospropofol Disodium: Accurately weigh 50 mg of Fospropofol Disodium and mix with ultrapure water to prepare a 50 mg / ml stock solution for later use.

[0147] 3) Chromatographic conditions: mobile phase: acetonitrile-0.1% trifluoroacetic acid; flow rate: 1.0 ml / min; column temperature: 25°C; fospropofol disodium (fluorescence spectrophotometer); injection volume: 10 μl; acquisition time: 12 minutes (fospropofol disodium)

[0148] 3 Experimental results

[0149] 1) Fospropofol disodium standard curve

[0150] like Figure 4 shown.

[0151] 2) In vivo metabolism detection of fospropofol disodium

[0152] Table 5. Changes of fospropofol disodium concentration in plasma of rats in each group with administration time

[0153]

[0154] The results are shown in Table 5 and Figure 5 shown.

[0155] 3) Fospropofol disodium drug-dose curve and elimination half-life

[0156] Table 6. Elimination half-life of fospropofol disodium in rats of each group

[0157]

[0158] Note: ANOVA P =0.65.

[0159] The results are shown in Table 6 and Figure 6-8 shown.

[0160] The above results indicate that the combined administration of lidocaine hydrochloride and fospropofol disodium does not significantly prolong the metabolism time of fospropofol disodium.

[0161] Experimental Example 4: In vitro stability evaluation of mixed drugs

[0162] 1 Experimental Materials

[0163] Reagents: lidocaine hydrochloride injection, fospropofol disodium, acetonitrile, methanol, trifluoroacetic acid, ultrapure water.

[0164] Experimental instruments and equipment: Waters 2695 high performance liquid chromatograph, 2996 UV spectrophotometer, 2475 fluorescence spectrophotometer, electronic balance.

[0165] 2. Experimental drug preparation

[0166] 1) Prepare a mixed drug with a concentration ratio of fospropofol disodium to lidocaine hydrochloride of 3:2. The concentration of fospropofol disodium in the mixed drug is 7.5 mg / ml, and the concentration of lidocaine hydrochloride is 5 mg / ml.

[0167] 2) Chromatographic analysis was performed at five time points, starting from immediately after thorough vortex mixing and continuing until 24 hours after mixing. For lidocaine hydrochloride, the time points were 0.5, 2, 6, 12, and 24 hours; for fospropofol disodium, the time points were 0.5, 2, 6, 16, and 24 hours.

[0168] 3 Chromatographic methods

[0169] Chromatographic conditions: mobile phase: acetonitrile-0.1% trifluoroacetic acid; flow rate: 1.0 ml / min; column temperature: 25°C; detection wavelength: 263 nm for lidocaine hydrochloride (UV spectrophotometer), fospropofol disodium (fluorescence spectrophotometer); injection volume: 10 μl; acquisition time: 7 min (lidocaine hydrochloride), 12 min (fospropofol disodium).

[0170] 4 Experimental results

[0171] 1) Concentration of mixed drug lidocaine hydrochloride

[0172] Table 7. Lidocaine hydrochloride concentrations measured at different time points in mixed drugs

[0173]

[0174] 2) Concentration of mixed drug fospropofol disodium

[0175] Table 8. Concentrations of fospropofol disodium in mixed drugs measured at different time points

[0176]

[0177] The above in vitro experimental results show that the combination of lidocaine hydrochloride and fospropofol disodium does not significantly affect the stability of the two drugs themselves.

[0178] In summary, the present invention provides a pharmaceutical composition comprising a local anesthetic and fospropofol disodium, and a combination drug, belonging to the field of pharmaceutical preparations. The pharmaceutical composition and the combination drug have both analgesic and sedative effects. Through additive or synergistic effects between the drugs, the onset time of fospropofol disodium can be shortened, the pharmacodynamic effect can be enhanced, the drug dosage can be reduced, the pH of the fospropofol disodium solution can be improved, adverse reactions during anesthesia induction can be alleviated, the number of medications required by anesthesiologists can be reduced, and the anesthesia induction process can be made more convenient, thereby achieving a more ideal anesthetic effect.

Claims

1. Use of a local anesthetic in the preparation of a medicament for ameliorating an adverse reaction caused by fospropofol disodium during anesthesia induction, wherein the adverse reaction is pruritus caused by fospropofol disodium, and the local anesthetic is lidocaine or a salt thereof.

2. The use according to claim 1, characterized in that The salt is hydrochloride, sulfate, citrate, succinate, maleate, glycolate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, levulinate, gluconate, glucuronate, lactate, malate, pyruvate, fumarate, tartrate, sulfonate, malonate, adipate, glutarate, glycerate, methacrylate, β-hydroxybutyrate, hydroxypropionate, ascorbate, aspartate or glutamate.

3. The use according to claim 1, characterized in that The medicine is in the form of tablets, capsules, powders, pills, granules, injections or emulsions.

4. The use according to claim 3, characterized in that The medicine is an injection.

5. Use of a local anesthetic and fospropofol disodium in the preparation of a combination drug for ameliorating an adverse reaction caused by fospropofol disodium during anesthesia induction, wherein the adverse reaction is pruritus caused by fospropofol disodium. The combination drug comprises a local anesthetic and fospropofol disodium in unit preparations of the same or different specifications for simultaneous or separate administration, and a pharmaceutically acceptable carrier; the local anesthetic is lidocaine or a salt thereof.

6. The use according to claim 5, characterized in that The salt is hydrochloride, sulfate, citrate, succinate, maleate, glycolate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, levulinate, gluconate, glucuronate, lactate, malate, pyruvate, fumarate, tartrate, sulfonate, malonate, adipate, glutarate, glycerate, methacrylate, β-hydroxybutyrate, hydroxypropionate, ascorbate, aspartate or glutamate.

7. The use according to claim 5, characterized in that In the combined drug, the mass ratio of the local anesthetic to fospropofol disodium is (1-10):

50.

8. The use according to claim 7, characterized in that In the combined drug, the mass ratio of the local anesthetic to fospropofol disodium is (5-7.5):50.

Images