WO2015113200A1

WO2015113200A1 - Hydrochloric tapentadol injection and preparation method thereof

Info

Publication number: WO2015113200A1
Application number: PCT/CN2014/071658
Authority: WO
Inventors: 吴仁荣
Original assignee: 江苏华泽医药科技有限公司; 吴仁荣
Priority date: 2014-01-28
Filing date: 2014-03-03
Publication date: 2015-08-06
Also published as: CN103735500B; CN103735500A

Abstract

A hydrochloric tapentadol injection and a preparation method thereof. The injection comprises an effective amount of an active ingredient of hydrochloric tapentadol salt or tapentadol alkali, a pharmaceutical carrier that is pharmaceutically acceptable for preparing an injection, and an additive.

Description

Ftacid tatapentan injection and preparation method thereof

First, the field of technology

The present invention relates to a new dosage form of tapentadol hydrochloride, in particular a small volume injection of tapentadol hydrochloride. The invention also relates to a process for the preparation of a small volume injection of tapentadol hydrochloride. Second, the background technology

On November 20, 2008, the FDA approved an oral release of tapentadol hydrochloride for the relief of moderate to severe acute pain. The approved specifications were 50 mg, 75 mg, and 100 mg, respectively, and the FDA was on August 25, 2011. Tetamistat hydrochloride sustained-release tablets were approved for the relief of moderate to severe acute pain, and the approved specifications were 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg, respectively. John Jenkins, director of the New Drugs Office of the FDA's Center for Drug Evaluation and Research, said in a FDA statement that the drug's approval provides health care professionals with an alternative to moderate to severe acute pain.

Tacitabine hydrochloride is a synthetic central system analgesic with mechanisms of opioid and non-opioid effects. It first stimulates the opioid peptide receptors in the brain, spinal cord and gastrointestinal tract, thereby improving the brain and body's anti-pain ability. Then, tapentadol hydrochloride inhibits the re-uptake of the brain's analgesic norepinephrine, thereby passing The above two ways to achieve its analgesic effect.

After the FDA approved the drug, Johnson & Johnson issued a statement that tapentadol hydrochloride is subject to review by the US Drug Enforcement Agency before it can be marketed. The FDA's statement added that acute pain is a symptom of many diseases that seriously affect the quality of life and physiology of patients with pain. Opioids are safe and effective for such specific patients, but can cause dependence, abuse and addiction. All patients should be used under the supervision of their professional health care practitioners to carefully observe whether abuse or addiction has occurred and decide to stop the administration. Johnson & Johnson said the approval was based on the results of several phase III clinical trials of tapentadol hydrochloride released at the 27th Annual Scientific Meeting of the American Pain Association in May this year. A total of more than 2,100 patients participated in clinical trials and the results showed that he was sprayed with hydrochloric acid compared with the placebo group. Significantly relieve pain caused by bunions, end-stage joint pain, low back pain, hip or knee pain. The most common adverse reactions associated with tapentadol hydrochloride include: nausea, dizziness, vomiting, and lethargy. Labeling of tapentadol hydrochloride includes: There is a risk of respiratory depression; when drinking alcohol, taking other opioids or illicit drugs, it can cause addictive inhibition of the central nervous system. Johnson &Johnson's statement emphasizes that no contraindications to opioids can be used with tapentadol hydrochloride, such as significant respiratory depression, acute or severe bronchial asthma, hypercapnia, patients with paralytic ileus, Use or a patient who has used a monoamine inhibitor in 14 days or the like. Patients with a history of epilepsy or who are at risk for epilepsy should be prescribed caution.

The chemical name of hetatadol is (-)-(lR, 2R)-3-(3-dimethylamino-ethyl-2-methyl-propyl)-phenol hydrochloride. Molecular formula: C ₁₄ H ₂₃ NOHCl, molecular weight: 257.8, its structural formula is as follows:

• HCI

CH3 This product is white or off-white crystalline powder; odorless, bitter. This product is very soluble in water, soluble in methanol, very slightly soluble in ethanol, and almost insoluble in acetone.

The results of the pharmacokinetic and metabolic studies of tapentadol hydrochloride are as follows:

Experimental animal studies: Tagatamine is a pure enantiomer, a variety of animal models show that oral absorption is rapid

(Tmax = 0.5 to 1 h), due to extensive first-pass metabolism, the absolute bioavailability of dogs and rats was lower. Only 3% and 8%, respectively, which was much lower than human oral administration. The mean half-life of plasma in male rats at 7 mg / kg iv was 0.5 h, but 300 mg / kg was longer (>2 h). The intravenous clearance was 228 ml I (min · kg) and the volume of dispense was 10.4. L / kg. The average half-life of dog intravenous injection and oral administration was 0.87 h and 3.7 h, respectively, and the IV volume was 10.9 L I kg, while the clearance rate totaled 145 ml I (min · kg). It binds less to all animal plasma proteins. From 11% of rabbits to 19.9% of rats, the plasma protein binding was 19% compared to humans.

Male rats received oral 14C-labeled tapentadol 150 mg / kg, and the radioactive doses recovered in urine and feces were 69% and 26%, respectively, and were completely eliminated within 48 h. In female rats, radioactive markers excreted in urine and feces, respectively About 94% and 5%. A high ratio of recovered doses in the urine. It is suggested that the absorbed dose is between 69% and 94%. The male beagle was orally administered 20 mg / kg, and the dose recovered in the urine accounted for 81% within 48 h, while 18% was in the stool.

In animals and humans, the main metabolic pathway of tapentadol is the second phase of glucuronidation. The first phase has less biotransformation. Studies have shown that his sprayed polyglucosaminide metabolite has no affinity for MOR, NE transporters or any other target. No activity was observed in the mouse appendix test injected intravenously or intracerebroventricularly. This is the obvious difference between his tapenta and other opioids, such as codeine or tilidine, and tramadol. All of these drugs require metabolic activation or morphine is converted to the more potent morphine-6-glucuronide. Because the analgesic activity of tapentadol is present in the parental molecule, the CYP2D6 enzyme does not require the conversion of active metabolites, thus reducing the likelihood of individual differences in the analgesic response to tapentadol. In vitro studies have shown that there is no interaction between tapentadol and cytochrome P-450 enzyme, and no inhibition or induction of human hepatocytes.

Human studies: healthy male volunteers took a single oral dose of ¹⁴ C hydrochloric acid with tapentadol 100 mg, which is equivalent to 85.86 mg of him. The actual acceptance of radioactive carbon is 1.867 MBq, or heptadol radioactivity ratio is 21.74 kBq I mg. The results showed that oral pentamidine absorption was rapid and peak plasma concentration (Cmax) was reached 1 to 2 h. The plasma appears predominantly in the form of bound metabolites, and the ratio of bound to unbound tapentadol is 24:1. The combined TAD peak concentration time (Tmax) was between 1.25 and 2.0 h, and the concentration of unconjugated tapentadol in all volunteers was very low (Cmax was 0.07 ± 0.03 g-eq base I ml), overall The area under the plasma concentration curve (AUC) O~120 (unbound + combined) of heptadol is about 64% of the total radioactive carbon AUC 0~120, and the whole blood radiocarbon Tmax is 1.25~1.5 h. Similar to morphine (20 to 30), the clearance rate of 1531 ml / min after intravenous injection is equivalent to hepatic blood flow (1400 ml I min). He sprayed 10~80 mg and 75~200mg respectively, and showed dose linearity after intravenous injection and oral administration. After 4 times of oral administration, it reached a steady state after about 25~30h. The average cumulative factor was 1.8, which was mainly sprayed by him. Multiple dosing intervals and apparent terminal half-lives were determined, and no changes in pharmacokinetic parameters were seen during dosing. ^{The 14} C-labeled tapenta mass balance study proved that he had more rapid excretion, more than 50% of the dose was discharged after 4 hours of administration, and excretion exceeded 95% within 24 hours. The radioactivity recovery rate of 48 hours of urine exceeded 98%. , apparent half-life (t) 3.93 h. Excretion is almost always through the kidneys, 99% is excreted by the urine, 69% of which are in the form of binding (glucuronide and sulphate), about 27% by other metabolites and 3 by pentoxide. Discharge, only 1% is excreted in the feces, by exhaling CO. Discharge was more negligible, which proved that the labeled drug was metabolically stable, and almost all of the dose was metabolized to an inactive conjugate (96%), and the excretion reached a complete equilibrium after about 5 days (mean recovery 99.9%). At present, in foreign countries, this product is only available in two dosage forms, tablet and oral liquid. There is no research report on the administration of any injection type.

The existing oral preparations have the first-pass effect of the liver, and have the disadvantages of low bioavailability, slow absorption distribution, and slow onset of action. Third, the content of the invention

The object of the present invention is to provide a small volume injection of tapentadol hydrochloride, which is directly intravenously injected, to overcome the above-mentioned deficiencies of the existing oral preparations, to expand the use of tapentadol hydrochloride, and to improve the dosage of tapentadol hydrochloride. The level of clinical use makes it suitable for diseases such as moderate to severe pain.

The tapentadol hydrochloride injection of the present invention comprises a pharmaceutically acceptable carrier and an additive comprising an effective amount of the active ingredient capitata salt or tapentadol and a pharmaceutically acceptable preparation for injection.

The pharmaceutically acceptable carriers and additives of the present invention are antioxidants, _P H value regulators, isotonicity adjusting agents and water for injection. Further, the pharmaceutically acceptable carrier and the additive may be selected from one or more of an antioxidant, a _P H value regulator, an isotonicity adjusting agent and water for injection; preferably, the pharmaceutically acceptable carrier and the additive are selected from the group consisting of antioxidants, _P H value regulator, isotonicity regulator and water for injection into the stomach.

The above-mentioned pharmaceutically acceptable carrier containing the present invention is not particularly limited as long as it is suitable for an injection. For example, the _P H value adjusting agent may be selected from one or more selected from the group consisting of sodium acetate trihydrate, sodium citrate, sodium carbonate, and the like, preferably sodium acetate trihydrate. The isotonicity adjusting agent may be selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, mannitol, sorbitol or dextran, preferably sodium chloride. The antioxidant may be selected from the group consisting of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite or sodium thiosulfate, preferably sodium hydrogen sulfite.

The amount of the pharmaceutically acceptable carrier to be used in the preparation is also not particularly limited and can be used within the range which does not affect the effect of the injection of the present invention. The pH of the tapentadol hydrochloride injection provided by the present invention is 5.5 to 6.5. In this pH range, the tapentadol hydrochloride injection is the most stable.

The osmotic pressure ratio of the tapentadol hydrochloride injection provided by the present invention is 0.9 to 1.1.

The present invention provides a solution of tapentadol hydrochloride, which contains 10 mg to 100 mg of tapentadol hydrochloride per ml of the injection, preferably 50 mg of tapentadol hydrochloride per ml of the injection. The object of the invention is achieved in that the preparation method comprises the following steps:

The preparation method of tapentadol hydrochloride injection comprises the following steps: Weigh the prescribed amount of tapentadol hydrochloride and a pharmaceutically acceptable carrier, add an appropriate amount of water for injection, and add 0.6% of the injection needle to the activated carbon, 50 ° C~ Stirring at 60 °C for 30 min, decarbonization by filtration, cooling to room temperature, adjusting the pH value of 5.5~6.5 with 1 mol/L sodium acetate trihydrate, adding water for injection to the whole amount, determining the intermediate content and pH value, and passing the 0.22μηι micro The membrane was filtered, filled in an ampule, and sterilized by autoclaving at 121 °C for 20 min.

Compared with the original oral preparation, the tapasalazine hydrochloride injection of the invention has the advantages of high bioavailability, good drug absorption, rapid distribution, quick onset, etc., and expands the use of tapentadol hydrochloride to improve the dosage. The clinical use level of tapentadol hydrochloride.

The natastatin hydrochloride injection solution of the invention is reasonable, the process is simple, and the stability is good. After accelerated test at 40 °C for 6 months, the appearance traits, _P H, active ingredient content and related substances did not change significantly.

The effective results of the present invention can be illustrated by the following experiments. Fourth, the specific real IS ^

The invention is further described in the following examples, which should not be construed as limiting the scope of the invention.

Example 1

Prescription:

Preparation Process:

Weigh the prescribed amount of tapentadol hydrochloride, add appropriate amount of water for injection, add 0.6% of the injection needle with activated carbon, stir at 50 ° C ~ 60 ° C for 30 min, filter decarbonization, cool to room temperature, with lmol / L Sodium acetate trihydrate is adjusted to pH 5.5~ 6.5, and water is added to the whole amount to determine the intermediate content and pH value. After passing the test, it is filtered through a 0.22μηι microporous membrane and filled in 2ml. In the ampoules, each bottle is filled with 2ml, and autoclaved at 121 °C for 20min, labelled, packaged, and finished after inspection. <Example 2

Prescription:

Preparation Process:

Weigh the prescribed amount of tapentadol hydrochloride, add appropriate amount of water for injection, add the prescribed amount of sodium bisulfite, dissolve, add 0.6% of the injection needle with activated carbon, stir at 50 ° C ~ 60 ° C for 30 min, filter Decarbonation, cooling to room temperature, adjusting the pH value of 5.5~6.5 with 1mol/L sodium acetate trihydrate, adding water for injection to the whole amount, determining the intermediate content and pH value, passing the filter after filtering through 0.22μηι microporous membrane, filling 2ml ampoules, 2ml per bottle, sterilized by hot pressing at 121 °C for 20min, labelled, packaged, and finished after inspection.

Example 3

Prescription:

Preparation Process:

The preparation method is the same as the embodiment except that the added auxiliary materials are different.

Example 4

Prescription:

Taprodamine Hydrochloride 75g

Sodium bisulfite 0.5g

Preparation Process:

The preparation method is the same as in the same embodiment except that the added auxiliary materials are different.

Prescription:

Preparation Process:

The preparation method is the same as the same embodiment 1 except that the added auxiliary materials are different.

Prescription:

Preparation Process:

prescription:

Preparation Process:

The preparation method was the same as in Example 1 except that the excipients added were different.

Example 8

Prescription:

Preparation Process:

Example 9: Accelerated Experimental Study

1. Sample lot number, source of tapentadol hydrochloride (Example 1, specification: 2ml: lOOmg; batch number: 20130601 20130602, 20130603): The company made it; The inner package is 2ml ampoules, plus small box, 2 boxes per box support.

2. Inspection conditions and sampling time According to the requirements of new drug declaration, the samples were placed in a constant temperature and humidity chamber with a temperature of 40 ° C and a relative humidity of 75% under the listed packaging conditions, and samples were taken at 1, 2, 3, and 6 months. Traits, clarity, pH, bacterial endotoxin, sterility, content and related substances, the results are shown in Table 1.

Table 1 Accelerated test results of tapentadol hydrochloride injection

Time Lot No. Character pH pH Clarity Bacterial endotoxin Sterility Related substances Content (%)

0 20130601 Almost colorless clear liquid 5.84 Qualified and qualified to meet the requirements 102.43 Month 20130602 Almost colorless clear liquid 5.92 qualified and qualified to meet the requirements of 101.01

20130603 Almost colorless clear liquid 5.88 Qualified Qualified Qualified Compliance 101.41

20130601 Almost colorless clear liquid 5.82 Qualified Qualified Qualified Compliance 102.33

20130602 Almost colorless clear liquid 5.91 Qualified Qualified Compliance Compliance 100.69 Months

20130603 Almost colorless clear liquid 5.85 Qualified Qualified Qualified Compliance 101.29

20130601 Almost colorless clear liquid 5.81 Qualified Qualified Qualified Compliance 101.86

20130602 Almost colorless clear liquid 5.89 Qualified Qualified Compliance Compliance 100.45 Month

20130603 Almost colorless clear liquid 5.81 Passed qualified Qualified Compliance 100.84

20130601 Almost colorless clear liquid 5.79 Qualified Qualified Qualified Compliance 101.62

20130602 Almost colorless clear liquid 5.87 Qualified Qualified Compliance Compliance 100.44 Months

20130603 Almost colorless clear liquid 5.80 Qualified Qualified Qualified Compliance 100.61

20130601 Almost colorless clear liquid 5.76 Qualified Qualified Qualified Compliance 101.09

20130602 Almost colorless clear liquid 5.82 Qualified Qualified Qualified Compliance 99.94 Months

20130603 Almost colorless clear liquid 5.75 qualified and qualified to meet the requirements of 100.11

3. Conclusion The present invention is an accelerated (40 ° C) test for 6 months in the simulated commercial packaging state of the present invention, and samples are detected at 1, 2, 3, and 6 months, respectively. There were no significant changes in the indicators.

Example 10: Local safety test of tapentadol hydrochloride injection

1. The clinical route of the administration of tapentadol hydrochloride is intravenous drip. For the special safety test of injection, the following indicators are specially designed: (1) The irritating effect of the injection of Taprofloxacin on the ear vein of rabbits (2) Systemic allergic test of chlorhexidine hydrochloride on guinea pigs; (3) Hydrolysis of catalyzed hemolytic test.

2. Test drug: Hydrochlorhexidine hydrochloride injection (Example 1), Specifications: 2 mL per strain: 100 mg.

3. Positive control drugs: Use fresh egg whites that can cause animal allergies.

4. Negative control drug: 0.9% sodium chloride injection.

5. Administration method: The administration route is the same as the clinical practice or the experimental method. Guinea pigs were sensitized by intraperitoneal injection and stimulated by intravenous administration; rabbits were administered by intravenous infusion of the ear.

6, dose and grouping

6.1 Rabbits: divided into test group and negative control group. The test drug group was administered at a dose of 15 mg/kg, the administration volume was 10 m·J kg, and the negative control group was given an equal volume of 0.9% sodium chloride injection. 6.2 Guinea pig: divided into test group, positive control group and negative control group. The test group was given a solution of tapentadol hydrochloride, the positive control group was given 5% fresh egg white, the negative control group was given 0.9% sodium chloride injection, and the sensitization volume was 0.5 mL/only. The dosage volume at the time of challenge was 2 mIJ.

6.3 Rabbit blood cells: 2% red blood cell suspension. When the test drug is used, it is diluted to a clinical use concentration according to the clinical use method (2 mL of tapentadol hydrochloride is added to 100 mL of sodium chloride injection, 2%), and is now ready for use. Five dose groups were set, and the dosing volumes were 0.5 mL, 0.4 mL, 0.3 mL, 0.2 mL, and 0.1 mL, respectively. The negative control group was 0.9% sodium chloride injection, the dosage volume was 2.5 mL, and the positive control group was distilled water. The volume of the addition solution was 2.5 mL.

7. Stimulating, allergic and hemolysis findings

7.1 Tapasotalt hydrochloride injection is not irritating to rabbit ear veins.

7.2 Tetrandre hydrochloride injection has no systemic allergic reaction to guinea pigs.

7.3 Tantastatin hydrochloride injection did not produce hemolysis and coagulation on rabbit red blood cells. ,

8. Conclusions: The above test results show that: Tapasanta hydrochloride hydrochloride has no vascular irritation, allergic and hemolysis.

I. Tribological stimulation test of rabbit ear veins with tapentadol hydrochloride injection

1, dose and grouping

The test group and the negative control group were given. The left ear of the rabbit was instilled with 0.9% sodium chloride injection, and the right ear was instilled with tapentadol hydrochloride injection for self-control. The test drug, tapentadol hydrochloride, is administered at a dose of 15 mg/kg, which is equivalent to 15 times the clinical dose. The negative control group was given an equal volume of 0.9% sodium chloride injection, and the administration volume was 10 mIJkg.

2, the method of administration

Three rabbits were placed in the rabbit box. The animals were slowly instilled with 0.9% sodium chloride injection in the left ear ear vein, and the taper hydrochloride injection was slowly instilled into the ear vein of the right ear. The instillation amount is lOm! Jkg, and the instillation speed is lm! Jmin (20 drops/min), 2 times a day for 5 consecutive days.

3. Indicator observation

The injection site of the rabbit was visually observed and recorded after 72 hours before and after the last administration, and the blood vessels and surrounding tissues at the injection site were observed to have redness and stimuli. At the end of the observation period, the rabbit was sacrificed and the ear piece was cut, 10% Neutral formaldehyde fixation, paraffin-embedded sections, HE staining, histopathological examination.

4, the results

All rabbits were intravenously infused with tapentadol hydrochloride for 5 days, and the injection site and the blood vessels and tissues away from the injection site were observed by the naked eye. No abnormal changes such as hemorrhage, congestion, edema, etc., and 0.9% chlorination with drip. There was no significant difference in the blood vessels of the control side of the sodium injection compared with the surrounding tissues.

Microscopically, the 0.9% sodium chloride injection control group and the tapentadol hydrochloride injection group had no wall injury in the ear vein, no thrombosis, no local tissue degeneration and necrosis, congestion and edema, and inflammatory cell infiltration around the blood vessels. There is focal or scattered inflammatory cell infiltration around only a few blood vessels.

5 Conclusion

Intravenous infusion of tapentadol hydrochloride has no stimulating effect on local blood vessels in rabbits.

2. Systemic allergy test of catarrhal hydrochloride injection on guinea pigs

1, dose and grouping

The test group, the positive control group and the negative control group were set. 6 guinea pigs per group. The test group was given a spray solution of tapentadol hydrochloride, the positive control group was given 5% fresh egg white, and the negative control group was given 0.9% sodium chloride injection. The volume of the drug was 0.5 mIJ when sensitized. The dose was 2 mIJ only when challenged.

2, sensitization and stimulation

20 guinea pigs, adapted for 3 days. Eighteen guinea pigs were randomly divided into 3 groups according to body weight, with 6 rats in each group. The remaining 2 guinea pigs are routinely used for the purpose of self-injection of a dose of the test drug after an injection of an allergic reaction to observe the presence or absence of similar allergic reactions caused by the test drug for judgment. Reference.

The test drug group was intraperitoneally injected with tapentadol hydrochloride, the positive control group was given 5% fresh egg white, and the negative control group was given 0.9% sodium chloride injection. The sensitized drug volume was 0.5 mIJ, every other day. Times, a total of 3 times. During the sensitization period, the state of each guinea pig was observed daily, and the body weight of the guinea pig was weighed on the first and last sensitization and on the day of the challenge, and the change in body weight was observed. On the 14th day and the 21st day after the last sensitization, 3 guinea pigs in each group were injected with the corresponding drugs intravenously, and the dose was 2 mL/only.

3. Observation indicators

Within 30 minutes after the challenge, the symptoms of each guinea pig were observed and recorded according to the symptoms shown in Table 1. The appearance and disappearance of symptoms were observed for a maximum of 3 hours.

Table 2 symptoms of allergic reactions

Result

During the sensitization period, the guinea pig's diet, activity and other conditions were normal, and the body weight increased. There was no significant difference in body weight of guinea pigs on the same day (see Table 3).

Table 4 Changes in body weight of guinea pigs (±S, g)

At 14d and 21d after the last administration, each guinea pig in the 5% fresh egg white positive control group showed a certain degree of agitation. Irritating, sneezing, sneezing, coughing, convulsions, gait instability, jumping, wheezing, convulsions, tidal breathing, shock to death, etc., and most of them die in about 3 minutes, the incidence of allergies is 100%, strong to Very strong positive allergic reaction. All of the guinea pigs in the 0.9% sodium chloride injection group and the tapentadol hydrochloride group had allergic symptoms and allergic reactions were negative. It indicated that the tantastatin hydrochloride injection had no systemic allergic reaction to guinea pigs (see Table 5).

Table 5 Results of systemic allergy test in guinea pigs with tapentadol hydrochloride injection (n=3)

,

There was no systemic sensitization response to guinea pigs with tapentadol hydrochloride.

Third, the specific hemolysis test of tapentadol hydrochloride injection

1. Preparation of red blood cell suspension

Take 10 mL of blood from the rabbit heart, place it in a sterile beaker, gently agitate the blood with a sterile glass rod for 5 min, remove fibrinogen, and make defibrillated blood, then add 100 mL of 0.9% sodium chloride injection and mix. Centrifuge (1500 rpm, lOmin), take the precipitated red blood cells, and wash it several times until the supernatant is not red. The obtained red blood cells are mixed with 0.9% sodium chloride injection into 2% red blood cell suspension for use.

2, adding liquid method

Take 7 tubes and number them. Tubes 1 to 5 are for the test tube, tube No. 6 is the negative control tube, and tube No. 7 is the positive control tube. Add 2% red blood cell suspension, 0.9%, as shown in Table 6. Sodium chloride injection, distilled water and 25% tapasal hydrochloride injection, mix well, immediately culture in (37±0.5) °C incubator, respectively, 15min, 30min, 45min, 60min, 2h after the thermostat , 3h carefully observed.

6 blood test (mL)

3,

The determination of hemolysis and red blood cell agglutination was carried out according to the criteria of "Technical Guidelines for Chemical Drug Irritant, Allergic and Hemolytic Research" to determine the effect of the test drug on hemolysis in vitro.

7

,

As a result, it can be seen from Table 7 that the distilled water control tube (positive control) is still a red clear solution, and the red blood cells are ruptured due to unequal internal and external osmotic pressure, and hemolysis occurs, and the red clear solution does not change. 0.9% sodium chloride injection control tube (negative control) and each of the tapentadol hydrochloride injection tube (test drug) in the observed time, the solution showed different degrees of stratification, the supernatant was colorless Clarity, no hemolysis occurs, red blood cells appear at the bottom of the test tube, and no red blood cell agglutination occurs. It is indicated that the tartapamide hydrochloride injection has no hemolysis effect on rabbit blood in the conventional in vitro test method (see Table 8).

Table 8 Results of external hemolysis test of tapentadol hydrochloride injection

Note: "Ten" is hemolysis, "一" is no hemolysis, "*" is red blood cell agglutination

5 Conclusion

There is no hemolysis effect on the blood of rabbits in vitro by tapentadol hydrochloride injection.

Claims

claims

1. Tapentadol hydrochloride injection, characterized in that the injection contains an effective amount of the active ingredient tapentadol hydrochloride salt or tapentadol base as well as pharmaceutically acceptable pharmaceutical carriers and additives for preparing injections .

2. The injection according to claim 1, characterized in that the pharmaceutical carrier and additive are selected from one or more of antioxidants, pH regulators, isotonic regulators and water for injection, Preferably, the pharmaceutical carrier and additive are at least two selected from the group consisting of antioxidants, _pH adjusters, isotonic adjusters and water for injection.

3. The injection according to claim 2, characterized in that the antioxidant is sodium sulfite, sodium bisulfite, sodium metabisulfite or sodium thiosulfate.

4. The injection according to claim 2, characterized in that the pH adjuster is sodium acetate trihydrate, sodium citrate or sodium carbonate, preferably sodium acetate trihydrate.

5. The injection according to claim 4, characterized in that the pH value of the injection is 5.5~6.5.

6. The injection according to claim 2, characterized in that the isotonic regulator is sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, mannitol, sorbitol alcohol or dextran.

7. The injection according to claim 6, characterized in that the osmotic pressure ratio of the injection is 0.9~1.1.

8. The injection according to claim 1, characterized in that each milliliter of the injection contains 10 mg to 100 mg of tapentadol hydrochloride.

9. The injection according to claim 8, characterized in that each milliliter of the injection contains 50 mg of tapentadol hydrochloride.

10. The preparation method of tapentadol hydrochloride injection includes the following steps: Weigh the formula amount of tapentadol hydrochloride and pharmaceutical carrier, add water for injection to dissolve, add 0.6% activated carbon for injection, 50°C Keep stirring at ~60°C for 30 minutes, filter and remove carbon, cool to room temperature, adjust the pH value to 5.5~6.5 with 1 mol/L sodium acetate trihydrate, add water for injection to the full amount, measure the intermediate content and pH value, and pass 0.22 μm after passing the test. Filter with microporous membrane, fill in ampoule, and autoclave at 121°C for 20 minutes.