A dexmedetomidine hydrochloride soluble microneedle and preparation method thereof

Abstract

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

[0001] The present invention relates to the field of pharmacy, and in particular to a dexmedetomidine hydrochloride soluble microneedle and a preparation method thereof. Background Art

[0002] Dexmedetomidine hydrochloride is a highly selective ∂2-adrenoceptor agonist. It binds to the ∂2 receptors in the brainstem and spinal cord, and has the advantages of rapid onset, short duration of action, no respiratory depression, and sedative and analgesic effects. A large number of literatures at home and abroad have confirmed that dexmedetomidine is used in children, and its anesthetic effect is safe and reliable. Its administration methods include intramuscular injection, intravenous injection, and nasal administration. At present, dexmedetomidine is only available as an injectable preparation, which is indicated for the sedation of mechanically ventilated patients who are intubated during treatment in an intensive care environment and the sedation of non-intubated patients before or during surgery and other procedures, and this must be given and supervised by experienced and licensed healthcare professionals intravenously. In addition, for a variety of reasons, the commercially available injectable preparations are not suitable for use as self-administered analgesics / sedatives, which limits their application to a certain extent.

[0003] Young children often fail to cooperate with certain auxiliary examinations before surgery, which affects the diagnosis results. The most common adverse reactions caused by the use of dexmedetomidine hydrochloride for preoperative sedation and continuous intravenous infusion sedation in children are hemodynamic, such as bradycardia and hypotension. Continuous intravenous infusion is also inconvenient for children to undergo various auxiliary examinations and sedation before surgery. Therefore, a soluble microneedle technology is developed to deliver dexmedetomidine hydrochloride percutaneously. The drug is delivered into the blood and into the systemic circulatory system by only piercing the stratum corneum barrier on the surface of the skin. It has the advantages of being painless, efficient, easy to operate and can be self-administered. This is a new drug delivery strategy that is more acceptable to children for preoperative sedation.

[0004] Soluble microneedles are commonly used preparations in the pharmaceutical field; however, the inventors found in their research that the soluble microneedles developed for dexmedetomidine hydrochloride have at least the following two defects: first, the onset time is slow, which is far less than the onset time of injection administration compared with dexmedetomidine hydrochloride injection; second, the relative bioavailability is low, which is also far less than that of injection administration compared with dexmedetomidine hydrochloride injection. Summary of the invention

[0005] In order to overcome at least one of the technical problems existing in the prior art, the present invention provides a dexmedetomidine hydrochloride soluble microneedle.

[0006] The technical problem to be solved by the present invention is achieved through the following technical solutions:

[0007] The invention provides a dexmedetomidine hydrochloride soluble microneedle, comprising a needle body and a substrate, wherein the needle body comprises dexmedetomidine hydrochloride and dextran.

[0008] The inventors surprisingly found in their research that the soluble microneedles made by combining dexmedetomidine hydrochloride with dextran can significantly shorten the onset time of the dexmedetomidine hydrochloride soluble microneedles due to the addition of dextran, and can also significantly improve the bioavailability of dexmedetomidine hydrochloride.

[0009] Preferably, the mass ratio of dexmedetomidine hydrochloride to dextran is 1:(1-10).

[0010] More preferably, the mass ratio of dexmedetomidine hydrochloride to dextran is 1:(3-5).

[0011] Preferably, the mass ratio of the needle body to the substrate is (0.5-3.5):100.

[0012] Further preferably, the mass ratio of the needle body to the substrate is (1-3):100;

[0013] More preferably, the mass ratio of the needle body to the substrate is (1~2):100.

[0014] Preferably, the substrate comprises polyvinyl pyrrolidone.

[0015] Further preferably, the polyvinyl pyrrolidone includes at least one of PVP K90, PVP K30 and PVP K60.

[0016] More preferably, the polyvinyl pyrrolidone is PVP K90.

[0017] The present invention also provides a method for preparing the above-mentioned dexmedetomidine hydrochloride soluble microneedle, which comprises:

[0018] Next steps:

[0019] S1: prepare needle solution and base solution;

[0020] S2: adding a needle solution to the mold, centrifuging, and injecting the needle solution into the microneedle negative mold;

[0021] S3: Recover the needle tip liquid, centrifuge it again, and place it in an oven for pre-drying;

[0022] S4: Add the base solution, centrifuge, and then dry again, demold, cut, and package to obtain the salt

[0023] Dexmedetomidine acid soluble microneedles.

[0024] Preferably, the needle solution in step S1 is prepared with water; the needle solution contains dexmedetomidine hydrochloride and dexmedetomidine hydrochloride.

[0025] The total mass fraction of glycosides is 15%~25%.

[0026] Further preferably, the total mass fraction of dexmedetomidine hydrochloride and dextran in the needle solution is 20% to 25%.

[0027] Preferably, the water is ultrapure water.

[0028] Preferably, in step S1, the base solution is prepared with alcohol; the mass fraction of polyvinyl pyrrolidone in the base solution is 10% to 35%.

[0029] Preferably, the alcohol is anhydrous ethanol.

[0030] More preferably, the mass fraction of polyvinyl pyrrolidone in the base solution is 20% to 35%.

[0031] Preferably, the specific step of preparing the base solution is to mix the alcohol and polyvinyl pyrrolidone uniformly. When the alcohol and polyvinyl pyrrolidone are mixed, the polyvinyl pyrrolidone swells.

[0032] Preferably, in the base solution preparation step, the mixing time is 6 to 24 hours.

[0033] Further preferably, in the base solution preparation step, the mixing time is 8 to 18 hours.

[0034] More preferably, in the base solution preparation step, the mixing time is 8 to 15 hours.

[0035] Preferably, in the step of preparing the base solution, mixing is performed by at least one of stirring, ultrasound and shaking.

[0036] Further preferably, in the step of preparing the base solution, mixing is performed by stirring.

[0037] Preferably, in the step of preparing the substrate solution, the stirring rate is 500-3000 rpm.

[0038] Further preferably, in the step of preparing the substrate solution, the stirring rate is 1000-3000 rpm.

[0039] More preferably, in the step of preparing the substrate solution, the stirring rate is 1500-2500 rpm.

[0040] Preferably, the centrifugation step is specifically: centrifuging at a centrifugal speed of 3800-4500 rpm for 5-40 min.

[0041] More preferably, the centrifugal speed is 4000-4500 rpm.

[0042] More preferably, the centrifugal speed is 4000~4300 rpm.

[0043] Preferably, the centrifugation time is 10 to 40 minutes.

[0044] More preferably, the centrifugation time is 10 to 30 min.

[0045] Preferably, the steps of preparing the needle solution are specifically as follows: mixing dextran with water to prepare an auxiliary material solution;

[0046] Then, the mixture is mixed with dexmedetomidine hydrochloride to prepare the needle solution.

[0047] Preferably, in the pre-drying step, the drying temperature is 20-60°C; further preferably, the drying temperature is 25-40°C; more preferably, the drying temperature is 25-35°C.

[0048] Preferably, in the pre-drying step, the drying time is 5 to 48 hours.

[0049] More preferably, the drying time is 5 to 24 hours.

[0050] More preferably, the drying time is 5 to 18 hours.

[0051] Preferably, the drying step is performed in a moisture-proof cabinet.

[0052] Preferably, the substrate drying step includes two processes: air bubble removal and drying.

[0053] Preferably, the degassing of bubbles in the substrate drying step is performed in a vacuum drying oven.

[0054] Preferably, the drying process in the substrate drying step has a drying temperature of 20-60°C.

[0055] More preferably, the drying temperature is 30-50°C.

[0056] More preferably, the drying temperature is 35-45°C.

[0057] Preferably, the drying time of the drying process in the base drying step is 5 to 48 hours.

[0058] More preferably, the drying time is 5 to 24 hours.

[0059] More preferably, the drying time is 5 to 18 hours.

[0060] Preferably, the drying process in the substrate drying step is carried out in an oven.

[0061] Beneficial effects: The present invention combines dexmedetomidine hydrochloride with dextran to form soluble microneedles, which can ensure that the peak time after microneedle transdermal delivery is equal to that of subcutaneous injection; it can achieve the effects of rapid release and rapid onset; in addition, it also has high bioavailability; therefore, the rapid release soluble microneedles in the present invention can reduce the discomfort of children taking the medicine while greatly improving their compliance, providing a new way of administration that can replace injection for preoperative sedation of children. DETAILED DESCRIPTION

[0062] The present invention is further explained below in conjunction with specific examples, but the examples do not limit the present invention in any form.

[0063] The specific implementation of the present invention is further described in detail below in conjunction with examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. If the manufacturer of the reagents or instruments used is not indicated, they are deemed to be conventional products that can be purchased commercially.

[0064] Example 1 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0065] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 1 below:

[0066] Table 1 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0067]

[0068] (1) Preparation of needle solution:

[0069] 1) Add the dextran in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0070] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and dextran of 23.08%.

[0071] (2) Preparation of base solution:

[0072] Weigh PVP K90 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a mass fraction of 33% of PVP K90.

[0073] (3) Preparation of soluble microneedles:

[0074] 1) Pipette 200 µL of the needle solution into the microneedle negative mold and centrifuge at 4000 rpm for 10 min at 0-10°C;

[0075] 2) Take out the mold, scrape off the residual needle solution on the upper layer, recycle it, and continue to centrifuge at 4000 rpm for 30 minutes at 0-10°C;

[0076] 3) Pre-dry the needle tip;

[0077] 4) Add the above substrate solution to the microneedle negative mold and centrifuge at 4000 rpm for 5 minutes at 0-10°C;

[0078] 5) Place in a vacuum drying oven to remove bubbles between the substrate and the needle tip under vacuum;

[0079] 6) Centrifuge at 4000 rpm for 5 min at 0-10 °C, place in an oven to dry for 12 h, and carefully peel off the mold to obtain dexmedetomidine hydrochloride soluble microneedles.

[0080] Example 2 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0081] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 2 below:

[0082] Table 2 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0083]

[0084] (1) Preparation of needle solution:

[0085] 1) Add the dextran in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0086] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and dextran of 15%.

[0087] (2) Preparation of base solution:

[0088] Weigh PVP K90 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a mass fraction of 30% of PVP K90.

[0089] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0090] Example 3 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0091] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 3 below:

[0092] Table 3 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0093]

[0094] (1) Preparation of needle solution:

[0095] 1) Add the dextran in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0096] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and dextran of 25%.

[0097] (2) Preparation of base solution:

[0098] Weigh PVP K60 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a mass fraction of 10% of PVP K60.

[0099] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0100] Example 4 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0101] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 4 below:

[0102] Table 4 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0103]

[0104] (1) Preparation of needle solution:

[0105] 1) Add the dextran in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0106] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and dextran of 20%.

[0107] (2) Preparation of base solution:

[0108] Weigh PVP K30 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a mass fraction of 20% of PVP K30.

[0109] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0110] Example 5 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0111] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 5 below:

[0112] Table 5 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0113]

[0114] (1) Preparation of needle solution:

[0115] 1) Add the dextran in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0116] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and dextran of 20%.

[0117] (2) Preparation of base solution:

[0118] Weigh PVP K90 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a mass fraction of 20% of PVP K90.

[0119] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0120] Comparative Example 1:

[0121] The composition of the injection in this example is shown in Table 6 below:

[0122] Table 6 Composition ratio of injection solution

[0123]

[0124] The preparation method of the injection in this example comprises the following steps:

[0125] (1) Preparation of solution:

[0126] 1) Add the formulated amount of dexmedetomidine hydrochloride into a centrifuge tube, add the formulated amount of normal saline, stir to dissolve, and obtain an injection solution;

[0127] 2) The injection solution is sterilized by high pressure to obtain an injectable injection solution.

[0128] Comparative Example 2 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0129] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 7 below:

[0130] Table 7 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0131]

[0132] (1) Preparation of needle solution:

[0133] 1) Add sodium hyaluronate in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0134] 2) Add dexmedetomidine hydrochloride in the above proportion to the excipient solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and sodium hyaluronate of 23.08%.

[0135] (2) Preparation of base solution:

[0136] Weigh the formulated amount of PVP K90 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a PVP K90 mass fraction of 33%.

[0137] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0138] Comparative Example 3 Preparation of Dexmedetomidine Hydrochloride Soluble Microneedles

[0139] The composition of the dexmedetomidine hydrochloride soluble microneedle is shown in Table 9 below:

[0140] Table 8 Composition ratio of dexmedetomidine hydrochloride soluble microneedles

[0141]

[0142] (1) Preparation of needle solution:

[0143] 1) Add polyvinyl alcohol in the above ratio into a centrifuge tube, add an appropriate amount of ultrapure water, stir and dissolve to obtain an auxiliary material solution;

[0144] 2) Add dexmedetomidine hydrochloride in the above proportion to the auxiliary material solution, stir and dissolve, and obtain a needle solution with a total mass fraction of dexmedetomidine hydrochloride and polyvinyl alcohol of 23.08%.

[0145] (2) Preparation of base solution:

[0146] Weigh the formulated amount of PVP K90 and add it to a 50 mL centrifuge tube. Add an appropriate amount of anhydrous ethanol and stir to swell overnight to obtain a base solution with a PVP K90 mass fraction of 33%.

[0147] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0148] Performance Test:

[0149] (1) Pharmacokinetic performance test:

[0150] According to ethical requirements, 12 male adult mice (Sprague-Dawley) weighing 180-220g were selected and divided into 4 groups, 3 mice in each group. They are Example 1 group and Comparative Example 1-3 groups, wherein Example 1 group uses the soluble microneedle in Example 1 for transdermal dorsal administration; Comparative Example 1 group uses the injection solution in Comparative Example 1 for subcutaneous dorsal administration; Comparative Example 2 and 3 groups use the soluble microneedle in Comparative Example 2 and 3 for transdermal dorsal administration.

[0151] The administration method is as follows: the back of the rat is depilated in advance, the microneedle is fixed on the probe of the tensile gauge, and the microneedle is applied to the back of the rat with a force of 100N and a speed of 500mm / min. The force is maintained for 5 minutes. After administration, the microneedle is fixed on the back of the rat for 2 hours and then removed. The dosage of each group is 350μg / rat; among them, the dosage of dexmedetomidine hydrochloride injection in the comparative example 1 group is 100ug / rat. 0.5 mL of blood is collected at 15min, 30min, 45min, 1h, 2h, 3h, 4h, 8h, 12h, 24h, and 48h after administration, and placed in a centrifuge tube with sodium heparin coated on the inner wall. The plasma is separated by centrifugation at 5000rpm for 10min, and then stored in a refrigerator at -20℃. The blood concentration of dexmedetomidine hydrochloride was detected by LC / MS, and the detected blood concentration of dexmedetomidine hydrochloride was recorded in Table 9. The drug-time curve was drawn according to the blood concentration of dexmedetomidine hydrochloride in Table 9, and the pharmacokinetic parameters were calculated. Among them, the pharmacokinetic parameters of Example 1 and Comparative Examples 1 to 3 are shown in Table 10.

[0152] Table 9 Blood concentration of dexmedetomidine hydrochloride in Example 1 and Comparative Examples 1 to 3 (in ng / mL)

[0153]

[0154]

[0155] Table 10 Pharmacokinetic parameters

[0156]

[0157] As can be seen from Tables 9 and 10, the blood drug concentration of the soluble microneedles prepared in Example 1 can be rapidly increased after transdermal administration, and its peak time is the same as that of the injection, and the blood entry speed is fast, which can achieve the effect of rapid release. However, after transdermal administration, the blood drug concentration increase rate and peak time of the soluble microneedles prepared in Comparative Examples 2 and 3 are far less than those of the soluble microneedles prepared in Example 1. In addition, the C maxand AUC 0-48h It is also significantly higher than the soluble microneedles prepared in Comparative Examples 2 and 3. This shows that the soluble microneedles prepared by combining dexmedetomidine hydrochloride with dextran can greatly shorten the onset time of dexmedetomidine hydrochloride soluble microneedles compared with adding other auxiliary ingredients, and can also greatly improve the bioavailability of dexmedetomidine hydrochloride.

[0158] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A dexmedetomidine hydrochloride soluble microneedle, comprising a needle body and a substrate, characterized in that: The needle body comprises dexmedetomidine hydrochloride and dextran; The substrate comprises polyvinyl pyrrolidone; The mass ratio of the needle body to the substrate is (0.5-3.5):100; The mass ratio of dexmedetomidine hydrochloride to dextran is 1:(1-10).

2. The dexmedetomidine hydrochloride soluble microneedle according to claim 1, characterized in that: The mass ratio of dexmedetomidine hydrochloride to dextran is 1:(3-5).

3. The dexmedetomidine hydrochloride soluble microneedle according to claim 1, characterized in that: The mass ratio of the needle body to the substrate is (1-3):

100.

4. The dexmedetomidine hydrochloride soluble microneedle according to claim 1, characterized in that: The mass ratio of the needle body to the substrate is (1~2):

100.

5. The dexmedetomidine hydrochloride soluble microneedle according to claim 1, characterized in that: The polyvinyl pyrrolidone includes at least one of PVP K90, PVP K30 and PVP K60.

6. The dexmedetomidine hydrochloride soluble microneedle according to claim 1, characterized in that: The polyvinyl pyrrolidone is PVP K90.

7. The method for preparing the dexmedetomidine hydrochloride soluble microneedle according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1: prepare needle solution and base solution; S2: adding a needle solution to the mold, centrifuging, and injecting the needle solution into the microneedle negative mold; S3: Recover the needle tip liquid, centrifuge it again, and place it in an oven for pre-drying; S4: adding the base solution, centrifuging, and then drying, demolding, cutting, and packaging again to obtain the dexmedetomidine hydrochloride soluble microneedles.

8. The preparation method according to claim 7, characterized in that: In step S1, the needle solution is prepared with water; the total mass fraction of dexmedetomidine hydrochloride and dextran in the needle solution is 15% to 25%.

9. The preparation method according to claim 7, characterized in that: The total mass fraction of dexmedetomidine hydrochloride and dextran in the needle solution is 20%~25%.

10. The preparation method according to claim 7, characterized in that: In step S1, the base solution is prepared with alcohol; the mass fraction of polyvinyl pyrrolidone in the base solution is 10% to 35%.

11. The preparation method according to claim 7, characterized in that: The mass fraction of polyvinyl pyrrolidone in the base solution is 20%~35%.

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