Dexmedetomidine freeze-dried composition and preparation method thereof

Abstract

The invention relates to biological medicine manufacturing, in particular to a dexmedetomidine freeze-dried composition and a preparation method thereof.The freeze-dried composition comprises active pharmaceutical ingredients and auxiliary materials, the active pharmaceutical ingredients in unit dosage are smaller than 200 micrograms, and the auxiliary materials comprise a skeleton supporting agent, an adhesive, edible essence and a sweetening agent; the skeleton supporting agent, the adhesive and the sweetening agent are all water-soluble. The freeze-drying composition disclosed by the invention can be disintegrated in the oral cavity, and the defect that the dosage of the taken medicine is greatly changed due to the condition that microgram-level effective component freeze-drying preparations stick to the bottom or fall off residues in the preparation process is overcome. In addition, the freeze-dried composition can be rapidly absorbed in the oral cavity and rapidly take effect, the first-pass effect is reduced, and the bioavailability is improved.

Description

Technical Field

[0001] The invention belongs to the field of biological medicine manufacturing, and particularly relates to a dexmedetomidine freeze-dried composition and a preparation method thereof. Background Art

[0002] Dexmedetomidine is a non-narcotic α-2 adrenergic receptor agonist with anti-sympathetic, sedative and analgesic properties. Dexmedetomidine can be administered via intravenous infusion, intramuscular injection, nasal drip, buccal mucosa or oral administration, and finding a more convenient way of administration has always been a clinical demand. However, dexmedetomidine has a significant first-pass elimination effect in the liver, so the oral bioavailability of dexmedetomidine in existing reports is only 16%.

[0003] CN106511273A discloses a sublingual spray dexmedetomidine composition, however, data analysis based on the subject's body weight, dosage, clinical observation, and blood sampling time indicates that sublingually administered dexmedetomidine has a Cmax of 0.914 ng / mL and a Tmax of 20 min.

[0004] TR201721065A2 discloses a lyophilized pharmaceutical preparation containing dexmedetomidine, which contains 0.01% to 50.00% of dexmedetomidine or a pharmaceutically acceptable salt thereof by weight of the total preparation, and also includes an excipient consisting of a lyoprotectant, a tension regulator, a pH regulator, an antimicrobial agent, a solubilizer, and the like. The lyophilized pharmaceutical preparation is mainly suitable for preparation into an injection reagent, and is generally reconstituted by adding water before injection.

[0005] CN108498469A discloses a dexmedetomidine hydrochloride freeze-dried powder and a preparation method thereof. The dexmedetomidine hydrochloride freeze-dried powder injection comprises 1 part of dexmedetomidine hydrochloride, 30-150 parts of lactose, 10-50 parts of propylene glycol and 0.1-0.9 parts of activated carbon, thereby solving the stability problem of dexmedetomidine hydrochloride in long-term storage.

[0006] CN108743551A discloses a dexmedetomidine hydrochloride freeze-dried powder injection and a preparation method thereof, which contains 1 part by weight of dexmedetomidine hydrochloride and 2-20 parts by weight of medium molecular weight dextran. Summary of the invention

[0007] The dexmedetomidine freeze-dried composition provided by the present invention can disintegrate in the oral cavity, thus overcoming the problem that the effective ingredients at the microgram level stick to the bottom or drop off during the preparation process, resulting in a large change in the dosage of the taken medicine.

[0008] In addition, the freeze-dried composition of the present invention is rapidly absorbed in the oral cavity, takes effect rapidly, reduces the first-pass effect, and improves bioavailability.

[0009] The technical solution adopted by the present invention is as follows:

[0010] The first aspect of the present invention provides a freeze-dried composition, comprising active pharmaceutical ingredients and excipients, wherein the active pharmaceutical ingredients in a unit dose are less than 200 micrograms, and the excipients include a skeleton support agent, an adhesive, an edible flavor and a sweetener, wherein the skeleton support agent, the adhesive and the sweetener are all water-soluble.

[0011] Specifically, the pharmaceutically active ingredient in a unit dose may be 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20 or 10 micrograms;

[0012] In a specific embodiment of the present application, the active pharmaceutical ingredient in the unit dose is 120 micrograms.

[0013] Furthermore, the skeleton support agent is selected from: one or more of sucrose, mannitol, sorbitol, maltitol, xylitol, lactitol, erythritol, isomalt, kapokose, maltose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminum silicate, glycine, alanine, aspartic acid, glutamic acid, hydroxyproline, isoleucine, leucine or phenylalanine.

[0014] In the present invention, when the skeleton support agent is sucrose, there is no need to add additional sweetener.

[0015] Furthermore, the adhesive is selected from: one or more of pullulan, alginate, hydroxypropyl methylcellulose, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan, hydroxypropyl methylcellulose or gelatin.

[0016] Furthermore, the edible flavor is selected from: mint flavor, sweet orange flavor, pineapple flavor, strawberry flavor, or a combination of two or more thereof. Preferably, the edible flavor is mint flavor.

[0017] Furthermore, the sweetener is selected from one or more of aspartame, acesulfame potassium, sucralose, aspartame, and sucrose.

[0018] Furthermore, the pharmaceutically active ingredient is dexmedetomidine or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutically acceptable salt is a hydrochloride, i.e., dexmedetomidine hydrochloride.

[0019] Furthermore, the auxiliary materials also include suspending agents and surfactants.

[0020] Furthermore, in parts by weight, the pharmaceutically active ingredient comprises 0.05 to 0.2 parts of dexmedetomidine or a pharmaceutically acceptable salt thereof, 5 to 10 parts of a skeleton support agent, 3 to 8 parts of a binder, 0.05 to 0.3 parts of an edible flavor, 0.05 to 0.2 parts of a sweetener, and 100 to 300 parts of water.

[0021] The present invention finds that the composition and ratio of auxiliary materials have an impact on the sticking condition of tablets (common dosage forms of freeze-dried compositions) during the preparation process. When the content of edible flavors in the auxiliary materials of the freeze-dried composition is not within an appropriate range, a thin layer of powder will adhere to the container (such as a common aluminum nest) during the preparation process of the tablets (common dosage forms of freeze-dried compositions). A specific auxiliary material ratio is required to solve this problem well.

[0022] Preferably, the pharmaceutically active ingredient dexmedetomidine or a pharmaceutically acceptable salt thereof comprises 0.1 to 0.2 parts, a skeleton support agent 6 to 9 parts, a binder 4 to 6 parts, an edible flavor 0.15 to 0.25 parts, a sweetener 0.08 to 0.12 parts, and water 150 to 250 parts.

[0023] In a specific embodiment of the present invention, the pharmaceutically active ingredient is 0.14-0.15 parts of dexmedetomidine or a pharmaceutically acceptable salt thereof, 7-9 parts of a skeleton support agent, 5-6 parts of a binder, 0.15-0.25 parts of an edible flavor, 0.09-0.1 parts of a sweetener, and 150-250 parts of water.

[0024] In a specific embodiment of the present invention, the freeze-dried composition comprises: 141.8 ug dexmedetomidine hydrochloride, 10 mg mannitol, 4 mg pullulan, 0.1 mg sucralose, and 0.2 mg mint powder flavor.

[0025] The second aspect of the present invention provides a method for preparing the composition according to the first aspect, comprising the following steps:

[0026] (I) Weighing the active ingredient of the drug and the excipients, dry mixing, adding water after mixing, stirring until a paste, adding the remaining water, emulsifying, making the system uniform, and obtaining a lyophilized solution;

[0027] (II) filling the lyophilized solution into a container;

[0028] (III) freeze-drying the container filled with the freeze-dried solution to obtain a freeze-dried composition;

[0029] Preferably, the step (III) further comprises pre-freezing before freeze-drying;

[0030] Preferably, the step (III) further comprises a sealing step;

[0031] Preferably, the weighed ambient humidity is less than or equal to 40% RH, for example, it can be 40% RH, 39% RH, 38% RH, 37% RH, 36% RH, and more preferably, the weighed ambient humidity is 36% RH.

[0032] Furthermore, the emulsification conditions are: rotation speed: 2000-3000 rpm, time 8-15 min;

[0033] And / or, the pre-freezing conditions are: temperature: -50 to -70°C, time 10 to 20 minutes;

[0034] And / or, the freeze-drying conditions are: the freeze-dried solution enters at -40 to -25°C, evacuates to ≤200ubar, maintains the vacuum, heats to -20 to -15°C, the initial heating time is 10 to 20 minutes, the initial holding time is 80 to 120 minutes, then heats to 15 to 30°C, heats again for 30 to 50 minutes, and holds again for 80 to 120 minutes;

[0035] And / or, the sealing condition is that the freeze-dried composition is sealed at 160-170°C.

[0036] Furthermore, the pharmaceutical composition is a sublingual tablet.

[0037] The third aspect of the present invention provides the use of the freeze-dried composition of the present invention in the preparation of sedative, anti-agitation, hypnotic and analgesic drugs.

[0038] Preferably, the drug is a sublingual preparation.

[0039] Beneficial effects of the present invention:

[0040] (1) The freeze-dried composition of the present invention overcomes the problem of microgram-level active ingredient freeze-dried compositions, which may cause large changes in the dosage of the drug to stick to the bottom or fall off during the preparation process, especially during the preparation of tablets. The preparation process does not stick to the container wall, has good uniformity, stable properties, and a high content of active ingredients.

[0041] (2) The freeze-dried composition of the present invention is rapidly absorbed in the oral cavity, takes effect quickly, reduces the first-pass effect, improves bioavailability, reduces side effects, and increases drug efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1a Shown is the product prepared in Example 1.

[0043] Figure 1b Shown is the product prepared in Example 1.

[0044] Figure 1c Shown is the product prepared in Example 1.

[0045] Figure 2a Shown is a front view of the product prepared from the raw materials of Recipe 1.

[0046] Figure 2b Shown is the back view of the product prepared from the raw materials of Formula 1.

[0047] Figure 2c Shown is a single particle image of the product prepared from the raw materials of recipe 1.

[0048] Figure 3a Shown is the front view of the product of Formulation 2.

[0049] Figure 3b Shown is the back view of the product of Formulation 2.

[0050] Figure 3c Shown is a photo of the aluminum nest of the product of Formula 2. DETAILED DESCRIPTION

[0051] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0052] In the present invention, the term "sublingual tablet" refers to a tablet that can be quickly dissolved when placed under the tongue, and the drug is absorbed through the sublingual mucosa to exert systemic effects. The drug and excipients of the sublingual tablet should be easily soluble and are mainly suitable for the treatment of emergencies.

[0053] In the present invention, the term "emulsification" refers to the process in which one phase of two immiscible solutions is dispersed in the other phase in the form of micro-droplets to form an emulsion. The quality of emulsification directly determines the stability and quality of the finished product. Through high-speed stirring and strong shearing effect on the material, the oil and water phases are fully contacted, mixed and dispersed, so that the particle size of the material is uniform.

[0054] In the present invention, the term "freeze drying" is also called vacuum freeze drying technology, which is a new drying method that freezes water-containing materials into solids and uses the sublimation properties of water under low temperature and low pressure conditions to dehydrate the materials at low temperature to achieve drying.

[0055] In the present invention, the term "batch content" refers to batch content (%) = actual content of active ingredient in finished drug product / theoretical content of active ingredient in finished drug product.

[0056] In the present invention, the term "intermediate" refers to the mixture after the preparation in step (I), or the mixture before freeze-drying in step (III).

[0057] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If no specific conditions are specified in the examples, the process is carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0058] Example 1 Formulation and process of freeze-dried composition

[0059] 1.1 Preparation formula of freeze-dried composition:

[0060] Table 1 shows the prescription of dexmedetomidine hydrochloride (lyophilized) sublingual tablets

[0061] Table 1

[0062]

[0063]

[0064] Among them, the amount of dexmedetomidine hydrochloride added must be calculated on a dry and pure basis: the formula is actual amount added = theoretical amount added / content / (1-water content).

[0065] 1.2 Preparation process:

[0066] Weighing: Weigh the raw materials and auxiliary materials into suitable containers (operate in a weighing room with an ambient humidity of 36% RH).

[0067] Liquid preparation: ① Place mannitol, pullulan, sucralose, mint powder essence and dexmedetomidine hydrochloride (wet weighing paper with water) in a suitable container, stir with a glass rod for 2 minutes, add a small amount of purified water, stir with a glass rod until it becomes a paste, and add the remaining purified water. ② Use an emulsifier to shear, speed: 2500rpm, time: 10 minutes.

[0068] Filling: Use a pipette, theoretically 0.2g / tablet, and fill into a 0.2ml aluminum nest.

[0069] Pre-freezing: Place the filled aluminum nests in a -60℃ refrigerator for 15 minutes. After pre-freezing, store them in the refrigerator until they are placed in the freeze dryer.

[0070] Freeze drying: Freeze drying was performed according to the parameters shown in Table 2.

[0071] Table 2

[0072] Plate temperature Heating time Maintenance time Vacuum degree -30℃ inlet - - - -30℃ vacuum - - ≤200ubar -15℃ 15min 90min ≤200ubar 25℃ 40min 90min ≤200ubar

[0073] Sealing: 160~170℃ sealing.

[0074] The product prepared by the present invention is specifically shown in Figures 1a to 1c It can be seen that the tablet form of the freeze-dried composition of the present invention is full and uniform.

[0075] Example 2 Optimization of freeze-dried composition components and preparation process

[0076] 2.1 Film type optimization

[0077] Table 3 Recipe 1

[0078]

[0079]

[0080] As shown in Table 3, the difference from Example 1 is that the amounts of the skeleton agent and the binder are different. The freeze-dried composition product prepared is as follows: Figure 2a , 2b As shown in Table 2c, it can be seen that the product using the skeleton agent and adhesive described in Table 3 is not full and has cracks.

[0081] 2.1.1 Optimize the dosage of skeleton agent and adhesive:

[0082] By changing the amounts of the skeleton agent and the binder in Formula 1, Formula 2 was obtained, as shown in Table 4. The freeze-dried composition was prepared using the preparation process of Example 1. It can be seen that Figure 3a and Figure 3b As shown in FIG. 1 , when the amount of the skeleton agent is 10 mg and the amount of the adhesive is 4 mg, the crack problem of the product is solved. However, Figure 3c As shown in Table 2, a thin layer of powder adheres to the aluminum cavity of Formula 2, which may be caused by insufficient amount of adhesive in the prescription, inappropriate proportion of auxiliary materials and sedimentation. The component formula was further optimized to obtain the formula shown in Table 1. After preparation using the process in Table 2, it was found that the problems of product cracks and product adhesion to the aluminum cavity were solved.

[0083] Table 4 Recipe 2

[0084]

[0085] Prescription information (based on dexmedetomidine), filling volume: 0.2g / tablet, liquid preparation volume: 40g; specification 120μg.

[0086] Note: The dosage of dexmedetomidine hydrochloride: 120×236.74 / (236.74-36.46)=141.8ug.

[0087] 2.2 Taste Optimization

[0088] Blank tablets with different amounts of sucralose (as shown in Table 5, the sucralose content was optimized and three parallel experiments were conducted) and mint powder flavor (as shown in Table 6, the flavor content was optimized and two parallel experiments were conducted) were prepared, and the taste was tasted. It was finally determined that the amount of sucralose was 0.1 mg and the amount of mint powder flavor was 0.2 mg, with a relatively light sweetness and a good taste.

[0089] Table 5 Optimized formula of sucralose content

[0090]

[0091]

[0092] Table 6 Optimized formula of flavor content

[0093]

[0094] 2.3 Preparation process optimization

[0095] 2.3.1 Original process (process one):

[0096] The product prepared according to the formula and conditions of Example 1 was weighed, and the tablet weight difference was -4.82% to 5.14%, the batch content was 94.7%, and the total impurity content was 0.189%. The product weight difference met the limit requirements, and the content test results were qualified, but the content was low (about 95%). There was only one impurity peak in the related substances (the detection method refers to Example 3, related substances 3.3), and the single impurity and total impurity were both 0.189%. The original process generally met the requirements, and the process can be further optimized. 2.3.2 Optimize weighing and filling processes:

[0097] In the weighing step of step (I), the humidity of the weighing room is 48% RH. During the weighing of the raw material drug, the raw material drug may absorb moisture and gain weight, and the raw material may adhere to the weighing paper due to moisture absorption, which may cause the raw material drug feeding amount to be low. The weighing paper is rinsed with pure water. The optimized humidity of the weighing room is 36% RH. At the same time, the content of the intermediate and the content of the finished product (i.e., the final prepared freeze-dried composition) are detected to determine whether the process affects the content. The results are shown in Table 7 in 2.3.3 (the optimized process is called process two).

[0098] Example 3 Property detection of freeze-dried composition

[0099] The freeze-dried composition prepared according to the method of Example 1 was tested:

[0100] 3.1 Evaluation Method

[0101] 3.2 Properties

[0102] Inspection method: visual observation

[0103] Limit requirements: This product is white or off-white round freeze-dried tablets.

[0104] 3.3 Related substances

[0105] Description of related substances in Dexmedetomidine Hydrochloride (public notice) (content)

[0106] (1) Solution preparation: Take an appropriate amount of the test solution (the freeze-dried composition prepared in Example 1), accurately weigh it, dissolve it in water and quantitatively dilute it to make a solution that theoretically contains about 0.1 mg per 1 ml.

[0107] Reference solution: Take an appropriate amount of dexmedetomidine hydrochloride reference substance, weigh accurately, dissolve in water and quantitatively dilute to a solution containing approximately 0.1 mg per 1 ml.

[0108] Chromatographic conditions: liquid chromatography was used, with a chromatographic column filled with octadecylsilane bonded silica gel (YMC-TriartC18 (4.6×150mm, 3μm)); 1.12g / L disodium hydrogen phosphate solution (pH adjusted to 7.5 with phosphoric acid)-acetonitrile (50:50) as the mobile phase, isocratic elution; flow rate was 1.0ml / min; column temperature was 30°C; detection wavelength was 214nm; injection volume was 10μl.

[0109] System suitability requirements: The number of theoretical plates calculated based on the dexmedetomidine peak is not less than 3000. The separation between the dexmedetomidine peak and the adjacent impurity peaks meets the requirements.

[0110] (2) Reproduce the results

[0111] The concentration of the test and reference solutions in this method is 0.1 mg / ml. The specification of this product is 120 μg. Sample dilution is difficult, so the concentration of this product is diluted to 0.12 mg / ml.

[0112] Blank solution: water;

[0113] The blank auxiliary material solution is an aqueous solution in which the formula in Example 1 does not contain dexmedetomidine hydrochloride.

[0114] (3) Conclusion

[0115] Using the above method, the chromatographic peaks can be effectively separated, and the peak shape is better, which is significantly improved compared with the previous method. There is no interference from auxiliary materials, and the main peak emerges at about 5.3 minutes.

[0116] 3.4 Moisture

[0117] Inspection method: Check according to the moisture determination method (Method 0832, General Rules of Part 4 of the Chinese Pharmacopoeia 2020 Edition).

[0118] Limit requirement: shall not exceed 7.0%.

[0119] Conclusion: Meets limit requirements.

[0120] 3.5 Weight Difference

[0121] Inspection method: Check according to the weight difference inspection method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0101 Tablets).

[0122] Limit requirement: ±7.5%.

[0123] The specific detection methods are as follows:

[0124] Take 20 freeze-dried orally disintegrating tablets prepared in Example 1, accurately weigh the total weight, and after obtaining the average tablet weight, accurately weigh each tablet separately. The weight of each tablet is compared with the average tablet weight. According to the provisions in Table 7, no more than one tablet shall exceed the weight difference limit, and no one tablet shall exceed the limit by 1 times.

[0125] Table 7

[0126]

[0127] Conclusion: Meets limit requirements.

[0128] 3.6 Disintegration time

[0129] Inspection method: Check according to the disintegration time inspection method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0921).

[0130] Limit requirement: 10s.

[0131] The sublingual tablet prepared in Example 1 of the present invention meets the requirements.

[0132] 3.7 Content determination

[0133] Test method: Same as 3.3 method in Example 3:

[0134] Diluent: Water

[0135] Reference solution (0.12 mg / ml): Take 12 mg of dexmedetomidine hydrochloride and put it into a 100 ml volumetric flask, add diluent to dissolve and dilute to the scale.

[0136] Test solution - intermediate (0.12 mg / ml): Take about 2 g of the intermediate prepared in Example 1 (equivalent to 1.2 mg of dexmedetomidine, 10 tablets), put it into a 10 ml volumetric flask, dilute to the scale with diluent, shake well and filter to obtain.

[0137] Test solution - finished product (0.12 mg / ml): Take 20 tablets of the freeze-dried composition prepared in Example 1, accurately weigh, take 10 tablets respectively into a 10 ml volumetric flask, first add 3 ml of diluent to disintegrate, then add diluent to dilute to the scale, shake well and filter to obtain.

[0138] Chromatographic conditions: Same as method 3.3.

[0139] Limit requirements: The intermediate content should be equivalent to 90% to 110% of the feed amount, and the finished product content should be 90.0% to 110.0% of the labeled amount.

[0140] The test results of Example 3 are summarized in Table 8:

[0141] Table 8

[0142]

[0143]

[0144] (Single impurity refers to the content of a single impurity, and total impurity refers to the content of all impurities)

[0145] Conclusion: The sample intermediate of the freeze-dried composition prepared in Example 1 passed the inspection; the properties, moisture, weight difference and disintegration time of the finished product all met the requirements. The content of the finished product was measured for the sample filled at a filling volume of 0.205g, and the data was 97.3%. When converted to a filling volume of 0.200g (i.e., minus the extra filling part), two sets of parallel data were tested, and the contents were 94.8% or 93.5%, respectively. Compared with the intermediate solution, the content was about 4% to 5% lower, which was consistent with the conclusion of 100% filling volume (0.205g filling volume).

[0146] Example 4 Pharmacokinetic Study of Lyophilized Composition

[0147] 4.1 Experimental groups and drug administration

[0148] Table 9 Experimental groups and administration methods

[0149]

[0150] Three dogs / group were fasted for 12 hours before receiving a single oral dose, and then food was resumed 4 hours after administration.

[0151] 4.2 Sample collection and processing

[0152] The blood sampling time points for Group 1 were as follows: before administration, 5min, 15min, 30min, 1h, 2h, 3h, 4h, 5h, and 6h.

[0153] The blood sampling time points for Group 2 and Group 3 were arranged as follows: before administration, 15min, 30min, 1h, 2h, 3h, 4h, 5h, and 6h.

[0154] 4.3 Experimental Results

[0155] Liquid chromatography was used to detect the content of dexmedetomidine hydrochloride in the samples at each blood collection time point, see Table 10.

[0156] Table 10

[0157]

[0158] After calculation, the main pharmacokinetic parameters are shown in Table 11.

[0159] Table 11

[0160] parameter unit Intravenous injection Freeze-dried composition Direct oral administration Kel (1 / h) 1.45±0.249 1.07±0.226 NA t1 / 2 (h) 0.488±0.0791 0.668±0.154 NA Tmax (h) 0.0833(0.0833,0.0833) 1.00(1.00,3.00) 1.00(0.500,1.00) Cmax (ng / mL) 11.6±2.95 3.17±0.940 0.0482±0.0308 AUClast (h*ng / mL) 8.49±2.25 8.40±1.74 0.0769±0.0652 AUCINF (h*ng / mL) 8.51±2.26 8.48±1.76 NA AUC_Extr (％) 0.184±0.0508 0.673±0.283 NA MRTINF (h) 0.804±0.0369 2.00±0.155 NA Vd (mL / kg) 844±130 2370±840 NA Cl (mL / h / kg) 1230±284 2420±447 NA F ％ NA 49.5±10.2 0.453±0.384

[0161] Experiments have found that the freeze-dried composition can significantly improve Cmax and bioavailability.

[0162] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A freeze-dried composition comprising a pharmaceutically active ingredient and an auxiliary material, characterized in that: The active pharmaceutical ingredient in a unit dose is less than 200 micrograms, and, by weight, the active pharmaceutical ingredient and excipients include: 0.05-0.2 parts of active pharmaceutical ingredient, 5-10 parts of skeleton support agent, 3-8 parts of adhesive, 0.05-0.3 parts of edible flavor, 0.05-0.2 parts of sweetener, and the active pharmaceutical ingredient is dexmedetomidine or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, characterized in that The skeleton supporting agent is mannitol.

3. The composition according to claim 1, characterized in that The binder is pullulan.

4. The composition according to claim 1, characterized in that The edible flavor is mint powder flavor.

5. The composition according to claim 1, characterized in that The sweetener is sucralose.

6. The composition according to claim 1, characterized in that The active pharmaceutical ingredients and auxiliary materials include: 0.05-0.2 parts of active pharmaceutical ingredients, 5-10 parts of mannitol, 3-8 parts of pullulan, 0.05-0.3 parts of mint powder flavor, and 0.05-0.2 parts of sucralose.

7. The composition according to claim 1, characterized in that In terms of weight, the active ingredient of the medicine is 0.1 to 0.2 parts, mannitol is 6 to 9 parts, pullulan is 4 to 6 parts, mint powder flavor is 0.15 to 0.25 parts, and sucralose is 0.08 to 0.12 parts.

8. The method for preparing the composition according to claim 1, characterized in that: The steps include: (I) Weighing the active ingredient of the drug and the excipients, dry mixing, adding water after mixing, stirring until a paste, adding the remaining water, emulsifying, making the system uniform, and obtaining a lyophilized solution; (II) filling the lyophilized solution into a container; (III) freeze-drying the container filled with the freeze-dried solution to obtain a freeze-dried composition; The weighed ambient humidity is less than or equal to 40% RH; In the weighing step, weighing paper is used, and the weighing is performed after the weighing paper is moistened with water.

9. The method according to claim 8, characterized in that The emulsification conditions are as follows: rotation speed: 2000-3000rpm, time 8-15min; the freeze-drying conditions are as follows: the freeze-dried solution enters at -40--25°C, evacuates to ≤200ubar, maintains the vacuum degree, heats to -20--15°C, the initial heating time is 10-20min, the initial holding time is 80-120min, then heats to 15-30°C, heats again for 30-50min, and holds again for 80-120min.

10. Use of the freeze-dried composition according to any one of claims 1 to 7 in the preparation of sedative, anti-agitation, hypnotic and analgesic drugs, wherein the drug is a sublingual preparation.

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