A kind of dexmedetomidine hydrochloride injection and its preparation processTechnical field
The invention belongs to field of medicine preparing technology, it particularly relates to a kind of dexmedetomidine hydrochloride injection andIts preparation process.
Background technique
Dexmedetomidine hydrochloride is a kind of efficient, highly selective α2Adrenoceptor agonists, earliest by FinlandOrion Pharma company and U.S. Abott company's joint research and development are developed, and the medicine is by acting on two kinds of adrenergic receptorsAnd have and resist sympathetic, analgesia and sedation, it is 8 times of clonidine effect.FDA ratify its for Intensive Care Therapy middle or short term (<24 is smallWhen) sedation and analgesia drug, especially in early days after surgery.It acts on two kinds of adrenergic receptors, passes through exciting presynaptic membraneα2Receptor, it is suppressed that the release of norepinephrine, and have ceased the conduction of pain signal；In addition, passing through exciting postsynaptic membraneReceptor, Dexmedetomidine inhibit sympathetic activity so as to cause the decline of blood pressure and heart rate.Both effects integrateIt can produce calm, alleviation anxiety, sympathetic inhibition and analgesic effect.
Dexmedetomidine hydrochloride is the active dextroisomer of Medetomidine, in many animals experiment, has no apparentToxic side effect.In order, curative effect is good and Small side effects, with other downern phases for clinical application since foreign countries' listing for the medicineThan with unique advantage.Although its is significant in efficacy at present, sales volume is very big, domestic market vacancy, but due to drug sheetThere is the problems such as visible foreign matters increase in the influence that body is easy light and metal ion.Therefore acceleration 6 is caused in study on the stabilityA month and long-term 9 months sample visible foreign matters, which increase, not can solve always.
Summary of the invention
In order to solve the above technical problems, that the present invention provides a kind of stability is good, convenient for long-term storage and clinical use is pacifiedFull dexmedetomidine hydrochloride injection and its preparation process.
A kind of dexmedetomidine hydrochloride injection of the present invention, the dexmedetomidine hydrochloride injection includes major ingredientAnd water for injection, the major ingredient include active constituent and auxiliary material；The auxiliary material includes osmotic pressure regulator and metal ion network mixture；The active constituent is dexmedetomidine hydrochloride, and the osmotic pressure regulator is sodium chloride.
A kind of dexmedetomidine hydrochloride injection of the present invention, matter of the dexmedetomidine hydrochloride in injectionAmount concentration is 0.01-0.02%；Mass concentration of the sodium chloride in injection is respectively 0.8-1%；The metal ionMass concentration of the complexing agent in injection is 0.001%-0.005%.
A kind of dexmedetomidine hydrochloride injection of the present invention, the metal ion network mixture be selected from sodium tartrate,One or more of natrium adetate, mosatil.
A kind of dexmedetomidine hydrochloride injection of the present invention, the metal ion network mixture are mosatil.
A kind of dexmedetomidine hydrochloride injection of the present invention, matter of the metal ion network mixture in injectionMeasuring concentration is 0.004%.
A kind of preparation method of dexmedetomidine hydrochloride injection of the present invention, the preparation method are specially：1)First by major ingredient and solvent formation solution admixed together；2) decarburization after addition activated carbon adsorption, detects semi-finished product after filtering, qualifiedIt is filling afterwards.
A kind of preparation method of dexmedetomidine hydrochloride injection of the present invention, the preparation method are specially：1)The water for injection for taking recipe quantity 95% cools the temperature to 60 DEG C -70 DEG C after boiling；2) recipe quantity chlorination is added in turn on agitatorSodium, stirring make it dissolve for 5 minutes；Dexmedetomidine hydrochloride is added, stirring makes it completely dissolved and be uniformly mixed for 10 minutes；3) again30 DEG C -50 DEG C are cooled to, the metal ion network mixture mixture of recipe quantity is added, stirring keeps it complete molten, 3% (w/ of major ingredient amount is addedW) active carbon stirring and adsorbing 15 minutes；4) it mends and adds to the full amount of water for injection, continue to stir lower circulation 15 minutes, with 0.5 μm of titaniumAfter stick and 0.22 μm of millipore filter filtering, in sample tap sample detection medical fluid content and pH value, 30 are maintained to fluid temperatureAfter DEG C -40 DEG C, stops stirring and simultaneously close cooling penstock；5) after detection is qualified, through 0.22 μm of millipore filter of the encapsulating third level,Filling, sealing, sterilizes 15 minutes in 121 DEG C；6) lamp inspection, packaging, obtain finished product.
Compared with prior art, dexmedetomidine hydrochloride injection of the present invention in high-temperature, illumination and is accelerating 6The moon and the ph of each embodiment, content, related material result after long-term 24 months are still qualified, illustrate that the quality of entire product is stablized.In addition, the preparation process of dexmedetomidine hydrochloride injection of the present invention is simple, cost is relatively low, is convenient for industrialized production.
Specific embodiment
Dexmedetomidine hydrochloride injection of the present invention and its preparation process are done below with reference to specific embodimentIt further illustrates, but the scope of protection of the present invention is not limited thereto.
Embodiment 1
Raw material：Dexmedetomidine hydrochloride (in terms of Dexmedetomidine) 0.2g, sodium chloride 18g, sodium tartrate 0.08g, fillingIt penetrates with water to 2000ml, is made 1000.
Preparation method：1) water for injection for taking recipe quantity 95% cools the temperature to 60 DEG C after boiling；2) turn on agitator,Recipe quantity sodium chloride is added, stirring makes it dissolve for 5 minutes；Dexmedetomidine hydrochloride is added, stirring makes it completely dissolved for 10 minutesAnd it is uniformly mixed；3) it is cooled to 30 DEG C again, the sodium tartrate of recipe quantity is added, stirring keeps it complete molten, 3% (w/ of major ingredient amount is addedW) active carbon stirring and adsorbing 15 minutes；4) it mends and adds to the full amount of water for injection, continue to stir lower circulation 15 minutes, with 0.5 μm of titaniumAfter stick and 0.22 μm of millipore filter filtering, in sample tap sample detection medical fluid content and pH value, 30 are maintained to fluid temperatureAfter DEG C, stops stirring and close cooling penstock；5) after detection is qualified, through 0.22 μm of millipore filter of the encapsulating third level, filling,Sealing sterilizes 15 minutes in 121 DEG C；6) lamp inspection, packaging, obtain finished product.
Embodiment 2
Raw material：Dexmedetomidine hydrochloride (in terms of Dexmedetomidine) 0.2g, sodium chloride 18g, mosatil 0.08g, twoHydrogen coniferyl alcohol γ-O- alpha-L-rhamnoside 0.02g, injects water to 2000ml, is made 1000.
Preparation method：1) water for injection for taking recipe quantity 95% cools the temperature to 70 DEG C after boiling；2) turn on agitator,Recipe quantity sodium chloride is added, stirring makes it dissolve for 5 minutes；Dexmedetomidine hydrochloride is added, stirring makes it completely dissolved for 10 minutesAnd it is uniformly mixed；3) it is cooled to 50 DEG C again, the mosatil and dihydro coniferyl alcohol γ-O- α-L- rhamnose of recipe quantity is addedGlycosides, stirring keep it complete molten, active carbon stirring and adsorbing 15 minutes of major ingredient amount 3% (w/w) are added；4) it mends and injects water to entirelyAmount continues to stir lower circulation 15 minutes, after 0.5 μm of stud and 0.22 μm of millipore filter filtering, in sample tap sample detectionMedical fluid content and pH value stop stirring and close cooling penstock after fluid temperature is maintained at 40 DEG C；5) after detection is qualified,Through 0.22 μm of millipore filter of the encapsulating third level, filling, sealing sterilizes 15 minutes in 121 DEG C；6) lamp inspection, packaging, obtain finished product.
Embodiment 3
Raw material：Dexmedetomidine hydrochloride (in terms of Dexmedetomidine) 0.2g, sodium chloride 18g, mosatil 0.08g, addWater for injection is made 1000 to 2000ml.
Preparation method：1) water for injection for taking recipe quantity 95% cools the temperature to 70 DEG C after boiling；2) turn on agitator,Recipe quantity sodium chloride is added, stirring makes it dissolve for 5 minutes；Dexmedetomidine hydrochloride is added, stirring makes it completely dissolved for 10 minutesAnd it is uniformly mixed；3) it is cooled to 50 DEG C again, the mosatil of recipe quantity is added, stirring keeps it complete molten, major ingredient amount 3% is added(w/w) active carbon stirring and adsorbing 15 minutes；4) it mends and adds to the full amount of water for injection, continue to stir lower circulation 15 minutes, with 0.5 μmAfter stud and 0.22 μm of millipore filter filtering, in sample tap sample detection medical fluid content and pH value, it is maintained to fluid temperatureAfter 40 DEG C, stops stirring and close cooling penstock；5) it after detection is qualified, through 0.22 μm of millipore filter of the encapsulating third level, fillsDress, sealing, sterilize 15 minutes in 121 DEG C；6) lamp inspection, packaging, obtain finished product.
Quality testing
Selection detection embodiment 1-3 obtained by dexmedetomidine hydrochloride injection ph and related substance, with to the present invention intoRow is further described and verifies.
1, influence factor is tested
Sample segment is respectively taken to be placed in high temperature (60 DEG C ± 5 DEG C), illumination (4500lx ± 500lx), high humidity embodiment 1,2,3(RH92.5%) 10 days under the conditions of, investigate temperature, illumination to character, pH, clarity of solution and the color of each embodiment injection,In relation to substance and changes of contents.Character, clarity of solution and color meet the requirements, and pH, investigate in relation to substance and changes of contentsIt the results are shown in Table 1 and table 2.
Table 1：Each embodiment is in high temperature, illumination and super-humid conditions ph variation in 10 days
| Ph value | When 0 | High temperature (60 DEG C ± 5 DEG C) | Illumination (4500lx ± 500lx) | High humidity (RH92.5%) |
| Embodiment 1 | 5.51 | 5.53 | 5.57 | 5.59 |
| Embodiment 2 | 5.43 | 5.44 | 5.44 | 5.42 |
| Embodiment 3 | 5.37 | 5.32 | 5.34 | 5.38 |
In terms of 10 days each embodiment high temperature, illumination, high temperature results.Various embodiments of the present invention all have higher in each conditionStability.
The related substance testing result of each embodiment content of table 2
Show each embodiment in high temperature 10 days, illumination 10 days and high from each embodiment content and related substance testing resultRelated substance increases less after 10 days warm, illustrates that each embodiment stability is high.
3, study on the stability
Dexmedetomidine hydrochloride injection obtained by each embodiment is put into 40 DEG C ± 2 DEG C, is accelerated under RH75% ± 5%Experiment investigation and 25 DEG C ± 2 DEG C, the lower progress long term test investigation of RH60% ± 2%.Investigation the results are shown in Table 3-8.
Table 3：Each embodiment accelerated test ph testing result
| Ph value | When 0 | Accelerate January | Accelerate 2 months | Accelerate March | Accelerate June |
| Embodiment 1 | 5.51 | 5.47 | 5.48 | 5.45 | 5.41 |
| Embodiment 2 | 5.43 | 5.41 | 5.39 | 5.41 | 5.40 |
| Embodiment 3 | 5.37 | 5.33 | 5.35 | 5.29 | 5.35 |
Table 4：The related substance testing result of each embodiment accelerated test
Table 5：Each embodiment accelerated test content detection result
Table 6：Each embodiment long term test ph testing result
| Ph value | When 0 | Long-term June | Long-term December | It is 24 months long-term |
| Embodiment 1 | 5.51 | 5.49 | 5.47 | 5.48 |
| Embodiment 2 | 5.43 | 5.43 | 5.42 | 5.43 |
| Embodiment 3 | 5.37 | 5.35 | 5.34 | 5.33 |
Table 7：The related substance testing result of each embodiment long term test
Table 8：Each embodiment long term test content detection result
Investigated in terms of result from each embodiment accelerated test and long term test, each embodiment accelerate June and it is 24 months long-term after it is eachEmbodiment ph, content, related material result are still qualified, it was demonstrated that prescription provided according to the present invention and preparation method thereof preparationDexmedetomidine hydrochloride injection formulation stability is high.To sum up the present invention, which is feasible, to be illustrated to the detection of each embodiment effect, the dexmedetomidine hydrochloride injection and preparation method thereof provided have that stability is good, preparation process is simple and cost compared withLow the characteristics of being convenient for industrialized production.