CN115227638B - A dexmedetomidine hydrochloride soluble microneedle and preparation method thereof - Google Patents
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Abstract
本发明涉及药学领域，具体公开了一种盐酸右美托咪定可溶性微针及其制备方法。所述的盐酸右美托咪定可溶性微针，包括针体和基底，所述针体包括盐酸右美托咪定和右旋糖苷。本发明将盐酸右美托咪定与右旋糖苷结合制成可溶性微针，能达到快速释放药物，起效时间与皮下注射给药相同，同时还具有较高的生物利用度，是可替代皮下注射给药的新型治疗策略，有望日后用于儿童术前检查时的镇静作用，避免了儿童对注射针头的恐惧，提高了患者的顺应性，同时也提供了一种微针经皮给药的快速起效的可能性。The present invention relates to the field of pharmacy, and specifically discloses a dexmedetomidine hydrochloride soluble microneedle and a preparation method thereof. The dexmedetomidine hydrochloride soluble microneedle comprises a needle body and a substrate, and the needle body comprises dexmedetomidine hydrochloride and dextran. The present invention combines dexmedetomidine hydrochloride with dextran to form a soluble microneedle, which can achieve rapid drug release, and the onset time is the same as that of subcutaneous injection. At the same time, it also has a high bioavailability, and is a new treatment strategy that can replace subcutaneous injection. It is expected to be used for the sedative effect of children during preoperative examinations in the future, avoiding children's fear of injection needles, improving patient compliance, and also providing a possibility of rapid onset of microneedle transdermal administration.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a dexmedetomidine hydrochloride soluble microneedle and a preparation method thereof.
Background
Dexmedetomidine hydrochloride is a high-selectivity ∂ -adrenergic receptor agonist, and has the advantages of quick response, short action time, no respiratory depression, sedation, analgesia and the like by combining with a brain stem action target spot blue spot core and a ∂ receptor of spinal cord. A great deal of literature at home and abroad proves that the dexmedetomidine is applied to children, and the anesthesia effect is safe and reliable. The administration modes include intramuscular injection, intravenous injection, nasal administration and the like. Dexmedetomidine is currently marketed only as an injectable formulation indicating sedation for patients initiating mechanical ventilation of the cannula during intensive care environmental treatment and sedation for non-cannula patients prior to or during surgery and other steps, and this must be administered and supervised intravenously by experienced and licensed healthcare professionals. Furthermore, commercially available injectable formulations are unsuitable for use as self-administered analgesics/sedatives for a number of reasons, such that their use is somewhat limited.
The young children often cannot cooperate to affect the diagnostic result when receiving certain auxiliary examinations prior to surgery. The dexmedetomidine hydrochloride is used for preoperative sedation and continuous intravenous infusion sedation of children, the most common adverse reactions caused by the use of the dexmedetomidine hydrochloride are in terms of blood flow dynamics, such as bradycardia, hypotension and the like, and continuous intravenous infusion is inconvenient for children to perform various auxiliary examination sedation before operation, so that the soluble microneedle technology is developed to deliver the dexmedetomidine hydrochloride through skin, and the medicine is delivered into blood to enter the systemic circulatory system under the condition of only penetrating through the stratum corneum barrier on the skin surface, and the preparation has the advantages of no pain, high efficiency, convenience in operation, self administration and the like. This is a novel dosing strategy that is more acceptable for pre-operative sedation in children.
The soluble microneedle is a common preparation in the field of medicines, but the inventor discovers that the soluble microneedle developed for the dexmedetomidine hydrochloride has at least two defects that the first effect time is slow and is far less than that of injection administration compared with the injection administration of the dexmedetomidine hydrochloride, and the second effect time is low relative bioavailability and is far less than that of injection administration compared with the injection administration of the dexmedetomidine hydrochloride.
Disclosure of Invention
In order to overcome at least one technical problem existing in the prior art, the invention provides a dexmedetomidine hydrochloride soluble microneedle.
The technical problems to be solved by the invention are realized by the following technical scheme:
the invention provides a dexmedetomidine hydrochloride soluble microneedle, which comprises a needle body and a substrate, wherein the needle body comprises dexmedetomidine hydrochloride and dextran.
The inventor surprisingly found in the research that the soluble microneedle prepared by combining the dexmedetomidine hydrochloride and the dextran can greatly shorten the acting time of the dexmedetomidine hydrochloride soluble microneedle due to the addition of the dextran, and can also greatly improve the bioavailability of the dexmedetomidine hydrochloride.
Preferably, the mass ratio of the dexmedetomidine hydrochloride to the dextran is 1 (1-10).
Further preferably, the mass ratio of the dexmedetomidine hydrochloride to the dextran is 1 (3-5).
Preferably, the mass ratio of the needle body to the substrate is (0.5-3.5): 100.
Further preferably, the mass ratio of the needle body to the substrate is (1-3) 100;
More preferably, the mass ratio of the needle body to the substrate is (1-2): 100.
Preferably, the substrate comprises polyvinylpyrrolidone.
Further preferably, the polyvinylpyrrolidone comprises at least one of PVP K90, PVP K30, PVP K60.
More preferably, the polyvinylpyrrolidone is PVP K90.
The invention also provides a preparation method of the dexmedetomidine hydrochloride soluble microneedle, which comprises the following steps of
The method comprises the following steps:
s1, preparing a needle body solution and a substrate solution;
s2, adding a needle solution into a mould, centrifuging, and injecting the needle solution into a microneedle female mould;
s3, recovering needle tip liquid, centrifuging again, and placing in an oven for pre-drying;
S4, adding a base solution, centrifuging, then drying, demolding, cutting and packaging again to obtain the salt
Dexmedetomidine soluble microneedles.
Preferably, the needle solution in the step S1 is prepared by water, and the dexmedetomidine hydrochloride in the needle solution
The total mass fraction of the glucoside is 15% -25%.
Further preferably, the total mass fraction of dexmedetomidine hydrochloride and dextran in the needle body solution is 20% -25%.
Preferably, the water is ultrapure water.
Preferably, the substrate solution in the step S1 is prepared from alcohol, and the mass fraction of polyvinylpyrrolidone in the substrate solution is 10% -35%.
Preferably, the alcohol is absolute ethanol.
Further preferably, the mass fraction of polyvinylpyrrolidone in the base solution is 20% -35%.
Preferably, the substrate solution is formulated by mixing the alcohol and polyvinylpyrrolidone uniformly. When alcohol and polyvinylpyrrolidone are mixed, polyvinylpyrrolidone swells.
Preferably, in the step of preparing the substrate solution, the mixing time is 6-24 hours.
Further preferably, in the step of preparing the base solution, the mixing time is 8-18 hours.
More preferably, in the step of preparing the base solution, the mixing time is 8-15 hours.
Preferably, in the step of preparing the base solution, at least one of stirring, ultrasonic and shaking is adopted for mixing.
Further preferably, in the step of preparing the base solution, the mixing is performed by stirring.
Preferably, in the step of preparing the base solution, the stirring speed is 500-3000 rpm.
Further preferably, in the step of preparing the base solution, the stirring rate is 1000 to 3000rpm.
More preferably, in the step of preparing the base solution, the stirring rate is 1500 to 2500rpm.
Preferably, the centrifugation step is specifically centrifugation for 5-40 min under the condition that the centrifugation rotating speed is 3800-4500 rpm.
Further preferably, the centrifugal speed is 4000 to 4500rpm.
More preferably, the centrifugal speed is 4000-4300 rpm.
Preferably, the centrifugation time is 10-40 min.
Further preferably, the centrifugation time is 10-30 min.
Preferably, the needle body solution is prepared by mixing dextran with water to obtain adjuvant solution;
then mixing with dexmedetomidine hydrochloride to obtain the needle solution.
Preferably, in the pre-drying step, the drying temperature is 20-60 ℃, further preferably, the drying temperature is 25-40 ℃, and still more preferably, the drying temperature is 25-35 ℃.
Preferably, in the pre-drying step, the drying time is 5-48 h.
Further preferably, the drying time is 5-24 hours.
More preferably, the drying time is 5-18 h.
Preferably, the drying step is carried out in a moisture proof box.
Preferably, the step of drying the substrate comprises two processes of bubble removal and drying.
Preferably, the exhausting bubble in the substrate drying step is performed in a vacuum drying oven.
Preferably, the drying temperature of the drying process in the substrate drying step is 20-60 ℃.
Further preferably, the drying temperature is 30-50 ℃.
More preferably, the drying temperature is 35-45 ℃.
Preferably, the drying time of the drying process in the substrate drying step is 5-48 h.
Further preferably, the drying time is 5-24 hours.
More preferably, the drying time is 5-18 h.
Preferably, the drying process in the substrate drying step is performed in an oven.
The invention has the beneficial effects that the dexmedetomidine hydrochloride and the dextran are combined to prepare the soluble microneedle, the peak reaching time after percutaneous delivery of the microneedle is equal to that of subcutaneous injection administration, the effects of quick release and quick effect can be achieved, and in addition, the quick release type soluble microneedle has higher bioavailability, so that the compliance of the quick release type soluble microneedle is greatly improved while the discomfort of children administration is reduced, and a novel route capable of replacing injection administration is provided for the administration mode of pre-operation children sedation.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way.
Specific implementations of the invention are described in further detail below with reference to examples, but the practice and protection of the invention is not limited thereto. It should be noted that the following processes, unless otherwise specified, are all realized or understood by those skilled in the art with reference to the prior art. The reagents or apparatus used were not manufacturer-specific and were considered conventional products commercially available.
EXAMPLE 1 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 1:
TABLE 1 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding the dextran according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of the dexmedetomidine hydrochloride and the dextran of 23.08%.
(2) Preparing a substrate solution:
And weighing PVP K90, adding the PVP K90 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K90 mass fraction of 33%.
(3) Preparation of soluble microneedles:
1) Sucking 200 mu L of the needle body solution into a microneedle female die, and centrifuging at 4000rpm for 10min at 0-10 ℃;
2) Taking out the die, scraping the residual needle body solution on the upper layer, recycling, and continuously centrifuging at the speed of 4000rpm for 30min at the temperature of 0-10 ℃;
3) Pre-drying the needle tip;
4) Adding the substrate solution into a microneedle female die, and centrifuging at 4000rpm for 5min at 0-10 ℃;
5) Placing the substrate and the needle point in a vacuum drying box, and removing bubbles between the substrate and the needle point in a vacuum environment;
6) Centrifuging at 4000rpm for 5min at 0-10 ℃, placing the mixture in an oven for drying for 12h, and carefully stripping the mold to obtain the dexmedetomidine hydrochloride soluble microneedle.
EXAMPLE 2 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 2:
TABLE 2 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding the dextran according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of the dexmedetomidine hydrochloride and the dextran of 15%.
(2) Preparing a substrate solution:
And weighing PVP K90, adding the PVP K90 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K90 mass fraction of 30%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
EXAMPLE 3 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 3:
TABLE 3 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding the dextran according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of the dexmedetomidine hydrochloride and the dextran of 25%.
(2) Preparing a substrate solution:
And weighing PVP K60, adding the PVP K60 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K60 mass fraction of 10%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
EXAMPLE 4 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 4:
Table 4 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding the dextran according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of 20% of the dexmedetomidine hydrochloride and the dextran.
(2) Preparing a substrate solution:
And weighing PVP K30, adding the PVP K30 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K30 mass fraction of 20%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
EXAMPLE 5 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 5:
TABLE 5 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding the dextran according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of 20% of the dexmedetomidine hydrochloride and the dextran.
(2) Preparing a substrate solution:
And weighing PVP K90, adding the PVP K90 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K90 mass fraction of 20%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
Comparative example 1:
the composition ratios of the injections in this example are shown in Table 6 below:
table 6 composition ratio of injection
The preparation method of the injection in the example comprises the following steps:
(1) Preparing a solution:
1) Adding the dexmedetomidine hydrochloride with the formula amount into a centrifuge tube, adding the physiological saline with the formula amount, and stirring for dissolution to obtain injection;
2) The injection is sterilized under high pressure to obtain injectable injection.
Comparative example 2 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 7:
TABLE 7 composition ratio of dexmedetomidine hydrochloride soluble microneedle
(1) Preparing a needle body solution:
1) Adding sodium hyaluronate into a centrifuge tube according to the proportion, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of 23.08% of the dexmedetomidine hydrochloride and the sodium hyaluronate.
(2) Preparing a substrate solution:
And (3) weighing PVP K90 with the formula amount, adding the PVP K90 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K90 mass fraction of 33%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
Comparative example 3 preparation of dexmedetomidine hydrochloride soluble microneedle
The composition ratios of the dexmedetomidine hydrochloride soluble microneedle are shown in the following table 9:
table 8 composition ratios of dexmedetomidine hydrochloride soluble microneedles
(1) Preparing a needle body solution:
1) Adding polyvinyl alcohol according to the proportion into a centrifuge tube, adding a proper amount of ultrapure water, stirring and dissolving to obtain an auxiliary material solution;
2) Adding the dexmedetomidine hydrochloride with the proportion into the auxiliary material solution, stirring and dissolving to obtain the needle body solution with the total mass fraction of 23.08% of the dexmedetomidine hydrochloride and the polyvinyl alcohol.
(2) Preparing a substrate solution:
And (3) weighing PVP K90 with the formula amount, adding the PVP K90 into a 50mL centrifuge tube, adding a proper amount of absolute ethyl alcohol, and stirring and swelling overnight to obtain a substrate solution with PVP K90 mass fraction of 33%.
(3) The preparation method of the soluble microneedle is the same as in example 1.
Performance test:
(1) Pharmacokinetic performance test:
according to ethical requirements, 12 male adult mice (Sprague-Dawley) are selected, and the weight of the mice is 180-220 g, and the mice are divided into 4 groups of 3 mice each. Example 1 and comparative examples 1 to 3, respectively, wherein the soluble micro needle of example 1 was used for transdermal back administration, the injection of comparative example 1 was used for subcutaneous back administration, and the soluble micro needle of comparative examples 2 and 3 was used for transdermal back administration.
The administration method comprises dehairing the back of the rat in advance, fixing the microneedle on a probe of a tension meter, and applying the microneedle to the back of the rat at a speed of 500mm/min under a force of 100N, wherein the force is maintained for 5min, fixing the microneedle on the back of the rat after administration for 2 hours, and removing the microneedle, wherein the administration dose of each group is 350 mug/dose, wherein the administration dose of each group of dexmedetomidine hydrochloride injection of comparative example 1 is 100 ug/dose. Blood is collected for 0.5 mL at 15min, 30min, 45min, 1h, 2h, 3h, 4h, 8h, 12h, 24h, 48h after administration, and placed in a centrifuge tube with inner wall coated with heparin sodium, centrifuged at 5000rpm for 10min to separate blood plasma, and stored in a refrigerator at-20deg.C. The blood concentration of dexmedetomidine hydrochloride was measured by LC/MS, and the measured blood concentration of dexmedetomidine hydrochloride was recorded in table 9, and pharmacokinetic parameters were calculated from the blood concentration of dexmedetomidine hydrochloride plotted on a pharmaceutical-time curve in table 9. The pharmacokinetic parameters of example 1 and comparative examples 1 to 3 are shown in table 10.
Table 9 blood concentration of dexmedetomidine hydrochloride (unit: ng/mL) of example 1, comparative example 1 to 3
TABLE 10 pharmacokinetic parameter Table
As can be seen from tables 9 and 10, the blood concentration of the soluble microneedle prepared in example 1 can be rapidly increased after transdermal administration, the peak time is the same as that of the injection, the blood injection speed is high, and the rapid release effect can be achieved. However, the rate of increase in blood concentration and the peak time thereof after transdermal administration of the soluble microneedles prepared in comparative examples 2 and 3 were far less than those of the soluble microneedles prepared in example 1. In addition, the soluble microneedles prepared in example 1 were also significantly higher in C max and AUC 0-48h than the soluble microneedles prepared in comparative examples 2 and 3. Compared with the soluble microneedle prepared by combining the dexmedetomidine hydrochloride and the dextran, the soluble microneedle prepared by adding other auxiliary material components can greatly shorten the acting time of the dexmedetomidine hydrochloride soluble microneedle, and can also greatly improve the bioavailability of the dexmedetomidine hydrochloride.
While the embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes may be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (11)
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