Cyproheptadine hydrochloride oral solution and preparation method thereof

Abstract

The invention discloses a cyproheptadine hydrochloride oral solution, which is prepared from cyproheptadine hydrochloride, hydroxypropyl-beta-cyclodextrin, a sweetening agent, sodium ethyl p-hydroxybenzoate, glycerol and a citric acid-sodium citrate buffer pair. The pharmaceutical composition has a crucial effect on the stability and other quality of an oral solution, after a stability test, the oral solution prepared from the pharmaceutical composition provided by the invention has the advantages of fewer impurities, stable quality and no turbid phenomenon, and the invention discloses a preparation method of the pharmaceutical composition.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, more particularly to a solution of cyproheptadine hydrochloride for oral administration and a preparation method thereof. BACKGROUND

[0002] Cyproheptadine hydrochloride is 1-methyl-4-(5H-dibenzo[a,d]cyclohepta-5-ylidene)piperidine hydrochloride hemihydrate, and its structural formula is shown as formula I.

[0003]

[0004] Cyproheptadine hydrochloride has an anti-5-hydroxytryptamine effect, and its H1 receptor antagonism is more than 5 times stronger than that of chlorpheniramine. It is clinically used for treating eczema, urticaria, skin itching and other diseases. Its anticholinergic effect can be used for treating pediatric bronchiolitis. CN118319853A discloses a pharmaceutical composition containing cyproheptadine hydrochloride and a preparation method thereof. The pharmaceutical composition comprises cyproheptadine hydrochloride, sucrose, anhydrous ethanol, glycerol, sodium benzoate, sodium saccharin, and citric acid. Since it contains anhydrous ethanol, it is not suitable for children. Since cyproheptadine hydrochloride has poor stability in liquid preparations, it is prone to degradation to produce impurities; turbidity, precipitation and other phenomena may occur during storage of the preparation; in addition, improper selection of pH regulators and bacteriostatic agents in conventional oral solutions can accelerate the degradation of the active ingredient, affecting the quality and safety of the preparation. The composition still has problems such as insufficient long-term stability and taste to be improved, and its preparation process is relatively complex, which is not conducive to industrial production.

[0005] CN112022827B discloses a fast-release pharmaceutical preparation of cyproheptadine hydrochloride and a preparation method thereof. The pharmaceutical preparation comprises an active layer with cyproheptadine hydrochloride as the active ingredient in the inner layer and a pH control layer in the outer layer. The pH control layer is a fast-release layer, and the pH control layer dissolves in water to produce a microenvironment with a pH of 3-6. This ensures that cyproheptadine hydrochloride has high solubility regardless of whether it is taken before or after a meal, facilitating absorption by the human body. The present application uses a sodium dihydrogen phosphate and citric acid buffer, which is composed of 20-25 parts by weight of sodium dihydrogen phosphate and 180-220 parts by weight of citric acid. In this high proportion of citric acid environment, the solution has very strong acidity and cannot produce a microenvironment with a pH of 3-6. Moreover, since the dosage form is a tablet, it is not suitable for young children.

[0006] Therefore, it is of important practical value to develop a cyproheptadine hydrochloride oral solution preparation with high stability, good taste and suitable for industrial production. SUMMARY

[0007] Based on the above reasons, the applicant has been committed to the expansion of the dosage form since obtaining the production license of cyproheptadine hydrochloride cream. Through repeated experiments, it is found that the conventional formula is easy to precipitate, easy to degrade and poor in taste. After creative labor, a new cyproheptadine hydrochloride oral solution and a preparation method thereof are obtained. The oral solution comprises cyproheptadine hydrochloride, hydroxypropyl-beta-cyclodextrin, stevioside, sodium ethyl p-hydroxybenzoate, glycerol, and a citric acid-sodium citrate buffer pair. In the research, the applicant unexpectedly found that the use of hydroxypropyl-beta-cyclodextrin and stevioside in the oral solution plays a crucial role in the stability of the oral solution. The oral solution prepared by the pharmaceutical composition has less impurities, stable quality and no turbidity phenomenon after stability test.

[0008] The application is realized by the following technical scheme.

[0009] A cyproheptadine hydrochloride oral solution, which is composed of cyproheptadine hydrochloride, hydroxypropyl-beta-cyclodextrin, a sweetener, sodium ethyl p-hydroxybenzoate, glycerol, and a citric acid-sodium citrate buffer pair.

[0010] The cyproheptadine hydrochloride oral solution is composed of the following raw materials by weight: 20-60 parts of cyproheptadine hydrochloride, 100-300 parts of hydroxypropyl-beta-cyclodextrin, 4-12 parts of a sweetener, 10-30 parts of sodium ethyl p-hydroxybenzoate, 50-150 parts of glycerol, an appropriate amount of a citric acid-sodium citrate buffer pair, and the balance of purified water, with a total weight of 50,000-150,000 parts.

[0011] The cyproheptadine hydrochloride oral solution is characterized in that it is composed of the following raw materials by weight: 40 parts of cyproheptadine hydrochloride, 200 parts of hydroxypropyl-beta-cyclodextrin, 8 parts of a sweetener, 20 parts of sodium ethyl p-hydroxybenzoate, 100 parts of glycerol, an appropriate amount of a citric acid-sodium citrate buffer pair, and the balance of purified water, with a total weight of 100,000 parts.

[0012] The cyproheptadine hydrochloride oral solution, wherein the sweetener is one of sucrose, saccharin, sodium saccharin, cyclamate, sucralose, acesulfame potassium, stevioside, aspartame, thaumatin, glycyrrhizin, mannitol, fructose, etc.

[0013] The cyproheptadine hydrochloride oral solution, wherein the sweetener is stevioside.

[0014] The cyproheptadine hydrochloride oral solution, wherein the weight ratio of citric acid to sodium citrate in the citric acid-sodium citrate buffer pair is 5-1:0.5-1.

[0015] The cyproheptadine hydrochloride oral solution, wherein the pH value of the oral solution is maintained in the range of 4.5-5.5.

[0016] The cyproheptadine hydrochloride oral solution is prepared by the following method:

[0017] (1) Take purified water, add hydroxypropyl-β-cyclodextrin, and stir under ultrasonic conditions to form a stable cavity structure, with the temperature controlled at 40-60°C;

[0018] (2) Add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0019] (3) Add stevioside to the inclusion compound formed in step (2), so that the stevioside is directionally adsorbed on the outer cavity surface, thereby forming an inclusion structure;

[0020] (4) Add sodium ethyl p-hydroxybenzoate, glycerol, and citric acid-sodium citrate buffer, make up the water content, stir until uniform, adjust the pH to the range of 4.5-5.5, and then fill, to obtain the product.

[0021] The cyproheptadine hydrochloride oral solution is treated under low-energy ultrasonic conditions of 20-40 kHz for 60-90 minutes, with the ultrasonic power controlled at 30-80 W and the temperature controlled at 50°C.

[0022] The cyproheptadine hydrochloride oral solution is treated under low-energy ultrasonic conditions of 30 kHz for 75 minutes, with the ultrasonic power controlled at 50 W and the temperature controlled at 50°C.

[0023] The oral solution prepared by the present application is superior to the comparative example in all aspects of taste; the accelerated stability investigation shows that the cyproheptadine hydrochloride oral solution of the present application is stable in quality and safe and controllable when the weight ratio of cyproheptadine hydrochloride to hydroxypropyl-β-cyclodextrin is 1:5, which is equal to the molar ratio of 1:1.1. The analysis reason is that the molecular structure of cyclodextrin is linked by more than 6 glucose through α-1, 4-glycosidic bond, which is in the form of a barrel. The hydrophobic cavity formed in the barrel can absorb small hydrophobic molecules or groups of certain size and shape to form a stable non-covalent complex. The cyclodextrins linked by six, seven and eight glucose monomers through α-1, 4-glycosidic bond are α-CD, β-CD and Y-CD respectively. β-CD is one of the best known inclusion materials, and is the most widely used in the three types. The hydroxyl (-OH) and the introduced hydroxypropyl (-CH2CHOHCH3) in hydroxypropyl-β-cyclodextrin make its outside have strong hydrophilicity. Since cyproheptadine hydrochloride is a yellowish crystalline powder, it tastes bitter and is easily soluble in methanol, soluble in chloroform, slightly soluble in ethanol and slightly soluble in water. In order to improve its bioavailability and solubility, hydroxypropyl-β-cyclodextrin is used for inclusion. In the water environment, the hydrophobic aromatic ring part of cyproheptadine hydrochloride will spontaneously drill into the hydrophobic cavity of hydroxypropyl-β-cyclodextrin in order to escape from the water. The chemical degradation site (such as aromatic ring) of cyproheptadine hydrochloride is embedded in the cavity of HP-β-CD, which is physically isolated from the degradation factors such as light, oxygen and H + or OH - ions in the external environment, thereby slowing down the hydrolysis, oxidation and other degradation reactions, effectively reducing the generation of related substances. And it can cover the bitter taste, so the effect is achieved at one stroke. In addition, the cyproheptadine hydrochloride molecule is loaded in the cavity of cyclodextrin, and then stevioside is added. Since the molecular structure of stevioside is relatively large, stevioside forms a strong hydrogen bond network with the hydroxyl / hydroxypropyl on the outer surface of the cyclodextrin cavity through the hydroxyl on its sugar chain, and is combined on the outer surface of the cyclodextrin cavity, thereby forming a stable complex. Therefore, stevioside not only serves as a flavoring agent, but also participates in the improvement of the stability of the preparation.

[0024] The preparation process of the present application also has significant effect. After obtaining the preliminary inclusion liquid of cyproheptadine hydrochloride-hydroxypropyl-β-cyclodextrin, it is treated under low-energy ultrasonic condition of 20-40 kHz for 60-90 minutes, and the ultrasonic power is controlled at 30-80 W. The microstructure of the inclusion compound is rearranged, the water content in the cavity is reduced, and a more compact and stable inclusion complex is formed. Since ultrasonic has the ability to promote the rearrangement of cyclodextrin inclusion structure, it can be used for weak energy activation in the system of the present application to obtain a more stable inclusion complex. The temperature is controlled at 40-60°C. If the temperature is too high, it will cause the rupture of β-cyclodextrin inclusion and cavity, thereby reducing the inclusion rate of cyproheptadine hydrochloride. DETAILED DESCRIPTION

[0025] The solutions of the present application will be explained below with examples. Those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be regarded as limiting the scope of the present application. The specific techniques or conditions not mentioned in the examples are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not mentioned by the manufacturer are all conventional products obtained by purchase.

[0026] Example 1:

[0027] Prescription: Cyproheptadine hydrochloride 40 g, hydroxypropyl-β-cyclodextrin 200 g, stevioside 8 g, sodium ethyl p-hydroxybenzoate 20 g, glycerol 100 g, citric acid-sodium citrate buffer pair as appropriate, and the balance is purified water, a total of 100000 g, the preparation method is:

[0028] (1) Take purified water, add hydroxypropyl-β-cyclodextrin, and stir under ultrasonic conditions. The ultrasonic conditions are 30 kHz low-energy ultrasonic conditions for 75 minutes, the ultrasonic power is controlled at 60 W, and the temperature is controlled at 50°C to form a stable cavity structure;

[0029] (2) Add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0030] (3) Add stevioside to the inclusion compound formed in step (2) to allow stevioside to be oriented adsorbed on the outer cavity surface, thereby forming an inclusion structure;

[0031] (4) Add sodium ethyl p-hydroxybenzoate, glycerol, and citric acid-sodium citrate buffer pair, make up the water content, stir uniformly, adjust the pH value to 5, and pour to obtain the product.

[0032] Example 2:

[0033] Prescription: Cyproheptadine hydrochloride 20 g, hydroxypropyl-β-cyclodextrin 300 g, stevioside 4 g, sodium ethyl p-hydroxybenzoate 30 g, glycerol 50 g, citric acid-sodium citrate buffer pair as appropriate, and the balance is purified water, a total of 50000 g, the preparation method is:

[0034] (1) Take purified water, add hydroxypropyl-β-cyclodextrin, and stir under ultrasonic conditions. The ultrasonic conditions are 20 kHz low-energy ultrasonic conditions for 90 minutes, the ultrasonic power is controlled at 30 W, and the temperature is controlled at 50°C to form a stable cavity structure;

[0035] (2) Add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0036] (3) to the inclusion compound formed in step (2) add stevioside, so that stevioside is oriented adsorbed on the surface of the outer cavity, thereby forming an inclusion structure;

[0037] (4) add sodium ethyl p-hydroxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water content, stir until uniform, adjust the pH value to 4.5, fill, and it is obtained.

[0038] Example 3:

[0039] Prescription: cyproheptadine hydrochloride 60g, hydroxypropyl-β-cyclodextrin 100g, stevioside 12g, sodium ethyl p-hydroxybenzoate 10g, glycerol 150g, citric acid-sodium citrate buffer pair in proper amount, and the balance is purified water, a total of 150000g, the preparation method is:

[0040] (1) take purified water, add hydroxypropyl-β-cyclodextrin, and form an inclusion liquid under the condition of stirring and ultrasonic treatment. The ultrasonic treatment is 60 minutes under the condition of low-energy ultrasonic treatment of 40kHz, the ultrasonic power is controlled at 80W, and the temperature is controlled at 50℃, to form a stable cavity structure;

[0041] (2) add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0042] (3) add stevioside to the inclusion compound formed in step (2), so that stevioside is oriented adsorbed on the surface of the outer cavity, thereby forming an inclusion structure;

[0043] (4) add sodium ethyl p-hydroxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water content, stir until uniform, adjust the pH value to 5.5, fill, and it is obtained.

[0044] Comparative Example 1:

[0045] Prescription: cyproheptadine hydrochloride 40g, hydroxypropyl-β-cyclodextrin 200g, stevioside 8g, sodium ethyl p-hydroxybenzoate 20g, glycerol 100g, citric acid-sodium citrate buffer pair in proper amount, and the balance is purified water, a total of 100000g, the preparation method is:

[0046] (1) take purified water, add hydroxypropyl-β-cyclodextrin, and form an inclusion liquid under the condition of stirring and ultrasonic treatment. The ultrasonic treatment is 60 minutes under the condition of low-energy ultrasonic treatment of 40kHz, the ultrasonic power is controlled at 80W, and the temperature is controlled at 50℃, to form a stable cavity structure;

[0047] (2) add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0048] (3) add stevioside to the inclusion compound formed in step (2), so that stevioside is oriented adsorbed on the surface of the outer cavity, thereby forming an inclusion structure;

[0049] (4) Add sodium ethylparaoxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water, stir evenly, adjust the pH value to 5, fill, and it is obtained.

[0050] Comparative Example 2:

[0051] Prescription: Cyproheptadine hydrochloride 40g, anhydrous ethanol 8g, sodium ethylparaoxybenzoate 20g, glycerol 100g, citric acid-sodium citrate buffer pair, the rest is purified water, a total of 100000g, the preparation method is:

[0052] Take anhydrous ethanol, add cyproheptadine hydrochloride to dissolve, then add sodium ethylparaoxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water, stir evenly, adjust the pH value to 5, fill, and it is obtained.

[0053] Comparative Example 3:

[0054] Prescription: Cyproheptadine hydrochloride 40g, hydroxypropyl-β-cyclodextrin 200g, sodium ethylparaoxybenzoate 20g, glycerol 100g, citric acid-sodium citrate buffer pair 350g, the rest is purified water, a total of 100000g, the preparation method is:

[0055] (1) Take purified water, add hydroxypropyl-β-cyclodextrin and stir under ultrasonic conditions. The ultrasonic conditions are 30kHz low-energy ultrasonic conditions for 75 minutes, with the ultrasonic power controlled at 60W and the temperature controlled at 50℃, to form a stable cavity structure;

[0056] (2) Add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0057] (3) Add sodium ethylparaoxybenzoate, glycerol, citric acid-sodium citrate buffer pair to the inclusion compound formed in step (2), make up the water, stir evenly, adjust the pH value to 5, fill, and it is obtained.

[0058] Comparative Example 4:

[0059] Prescription: Cyproheptadine hydrochloride 40g, anhydrous ethanol 8g, stevioside 8g, sodium ethylparaoxybenzoate 20g, glycerol 100g, citric acid-sodium citrate buffer pair, the rest is purified water, a total of 100000g, the preparation method is:

[0060] Take anhydrous ethanol, add cyproheptadine hydrochloride to stir and dissolve, then add stevioside, sodium ethylparaoxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water, stir evenly, adjust the pH value to 5, fill, and it is obtained.

[0061] Comparative Example 5:

[0062] Prescription: cyproheptadine hydrochloride 40 g, hydroxypropyl-β-cyclodextrin 200 g, sucrose 8 g, sodium ethyl p-hydroxybenzoate 20 g, glycerol 100 g, citric acid-sodium citrate buffer pair as appropriate, and the balance is purified water, a total of 100000 g, the preparation method is:

[0063] (1) Take purified water, add hydroxypropyl-β-cyclodextrin and stir under ultrasonic conditions. The ultrasonic conditions are 30 kHz low-energy ultrasonic conditions for 75 minutes, the ultrasonic power is controlled at 60 W, and the temperature is controlled at 50°C to form a stable cavity structure;

[0064] (2) Add cyproheptadine hydrochloride to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound;

[0065] (3) Add sucrose to the inclusion compound formed in step (2);

[0066] (4) Add sodium ethyl p-hydroxybenzoate, glycerol, citric acid-sodium citrate buffer pair, make up the water content, stir uniformly, adjust the pH value to 5, and pour to obtain the product.

[0067] Experimental Example 1: Taste evaluation

[0068] A group of 30 people evaluated the oral solutions prepared in Examples 1-3 and Comparative Examples 1-4 according to the taste evaluation, and scored from sweetness, bitterness masking degree and overall acceptance (full score 10 points), the results are as follows:

[0069] Table 1 Taste evaluation results

[0070] Group Sweetness Score Bitterness Masking Score Overall Acceptability Example 1 9.0 9.0 9.0 Example 2 9.4 9.2 9.3 Example 3 7.1 6.2 7.4 Comparative Example 1 8.9 8.7 8.5 Comparative Example 2 5.4 5.7 4.6 Comparative Example 3 6.2 6.1 5.1 Comparative Example 4 7.5 7.3 6.8 Comparative Example 5 9.2 9.2 8.9

[0071] The above table shows that the cyproheptadine hydrochloride prepared in Example 1-2 has good scores in sweetness, bitterness masking and overall acceptance. Example 3 cannot completely mask the bitterness due to insufficient amount of cyclodextrin. Comparative Example 1 has poor bitterness masking effect due to insufficient cyclodextrin inclusion of cyproheptadine hydrochloride prepared at room temperature. Comparative Example 2 does not use cyclodextrin inclusion and stevioside, so it tastes bitter and has the worst overall acceptance. Comparative Example 3 only uses cyclodextrin inclusion without forming an inclusion structure with stevioside. Comparative Example 4 only uses stevioside, and both the sweetness score and the bitterness masking score are poor. Comparative Example 5 uses cyclodextrin inclusion and sucrose as a sweetener, and both the sweetness score and the bitterness masking score are acceptable.

[0072] The results show that the oral solution prepared in Example 1-2 of the present application is superior to Comparative Examples 1-5 in terms of taste. Example 2 has a higher amount of cyclodextrin, which is more expensive and needs to be further observed.

[0073] Experimental Example 2: Accelerated stability study

[0074] The samples of Examples 1-3 and Comparative Example 1-5 were subjected to accelerated stability test (condition: 40℃±2℃ / relative humidity 75%±5%), and samples were taken for testing at 0 month, 1 month, 3 months and 6 months, respectively.

[0075] Content and related substance testing method: refer to the previous research method of the applicant company [Wu HQ, Chen CX. Determination of related substances of cyproheptadine hydrochloride by high performance liquid chromatography [J]. Journal of Pharmacy Practice, 2017, 35(01): 60-63+69.], chromatographic column: Agilent Eclipse XDB-C18 column (4.6mm*250mm, 5μm). Mobile phase: acetonitrile-buffer [weigh about 2.16g of octane sulfonic acid sodium, add about 500ml of water, dissolve and shake well. Add 10.0ml of glacial acetic acid and 5.0ml of triethylamine, add water to 1000ml, shake well, and adjust the pH to 7.0 with triethylamine (85:15, V / V)]; flow rate: 1.0ml / min, detection wavelength: 286nm, injection volume: 10μl, column temperature: 25℃.

[0076] Experimental materials: cyproheptadine hydrochloride reference substance (USP); impurity A (cyproheptadine related substance A) reference substance (EP), impurity B (amitriptyline related substance A) reference substance and impurity C (cyproheptadine related substance C) reference substance are all from Changzhou Sanyao Pharmaceutical Co., Ltd.

[0077] The results are as shown in Table 2 below:

[0078] Table 2: Results of accelerated stability study of each sample

[0079]

[0080]

[0081] The above table shows that the cyproheptadine hydrochloride oral solution of the present application is still stable in quality after 6 months of accelerated stability test (condition: 40℃±2℃ / relative humidity 75%±5%) compared with Comparative Examples 1-4, wherein the appearance is colorless and clear, the solution pH value is stable, the total impurities are not more than 0.6%, and the content is basically unchanged. In Example 2, the use of hydroxypropyl-β-cyclodextrin is too large, which increases the viscosity of the liquid and leads to turbidity and affects the content. In Example 3, the use of hydroxypropyl-β-cyclodextrin is too small, which leads to incomplete inclusion and also causes turbidity of the solution and affects the content of the main drug after 6 months. In Comparative Example 1, the cyclodextrin inclusion liquid is prepared at room temperature without ultrasonic treatment, which leads to insufficient inclusion of cyproheptadine hydrochloride, resulting in turbidity of the solution, decrease of the content and increase of impurities after 6 months. In Comparative Example 2, cyclodextrin inclusion is not used, and stevioside is not used, which leads to turbidity of the solution, decrease of the content and increase of impurities after 3 months. In Comparative Example 3, only cyclodextrin inclusion is used, which does not form an inclusion structure with stevioside, resulting in poor stability, turbidity of the solution, decrease of the content and increase of impurities after 6 months. In Comparative Example 4, only stevioside is used, which leads to turbidity of the solution, decrease of the content and increase of impurities after 3 months. In Comparative Example 5, cyclodextrin inclusion is used, and sucrose is used as a sweetener, which cannot form a stable structure, resulting in decrease of the content and increase of impurities after 3 months. Therefore, the cyproheptadine hydrochloride oral solution of the present application is stable in quality, safe and controllable when the weight ratio of cyproheptadine hydrochloride to hydroxypropyl-β-cyclodextrin is 1:5, which is equivalent to a molar ratio of 1:1.1, and the participation of stevioside in the inclusion structure can selectively inhibit the generation rate of impurities, thus belonging to an unpredictable technical effect.

[0082] The above embodiments are only used to illustrate the present application, but not to limit the present application. Although the present application is explained in detail with reference to the embodiments, those skilled in the art should understand that various combinations, modifications or equivalent replacements of the technical solutions of the present application do not deviate from the spirit and scope of the present application, and should be covered in the scope of the claims of the present application.

Claims

1. A solution of cyproheptadine hydrochloride for oral administration, characterized in that, The oral solution is composed of cyproheptadine hydrochloride, hydroxypropyl-β-cyclodextrin, sweetening agent, sodium ethyl p-hydroxybenzoate, glycerol, and citric acid-sodium citrate buffer.

2. The racepinephrine hydrochloride oral solution according to claim 1, wherein The oral solution is composed of 20-60 parts by weight of cyproheptadine hydrochloride, 100-300 parts by weight of hydroxypropyl-β-cyclodextrin, 4-12 parts by weight of sweetening agent, 10-30 parts by weight of sodium ethyl p-hydroxybenzoate, 50-150 parts by weight of glycerol, and an appropriate amount of citric acid-sodium citrate buffer, with the balance being purified water, totaling 50,000-150,000 parts by weight.

3. The racepinephrine hydrochloride oral solution of claim 1, wherein, The oral solution is composed of 40 parts by weight of cyproheptadine hydrochloride, 200 parts by weight of hydroxypropyl-β-cyclodextrin, 8 parts by weight of sweetening agent, 20 parts by weight of sodium ethyl p-hydroxybenzoate, 100 parts by weight of glycerol, and an appropriate amount of citric acid-sodium citrate buffer, with the balance being purified water, totaling 100,000 parts by weight.

4. The racepinephrine hydrochloride oral solution of claim 1, wherein, The sweetening agent in the oral solution is one of sucrose, saccharin, sodium saccharin, cyclamate, sucralose, acesulfame potassium, stevioside, aspartame, thaumatin, glycyrrhizin, mannitol, and fructose.

5. The racepinephrine hydrochloride oral solution of claim 4, wherein the solution is isotonic. The sweetening agent in the oral solution is stevioside.

6. The racepinephrine hydrochloride oral solution of claim 1, wherein, The weight ratio of citric acid to sodium citrate in the citric acid-sodium citrate buffer is 5-1:0.5-1.

7. The racepinephrine hydrochloride oral solution of claim 1, wherein, The pH value of the oral solution is maintained in the range of 4.5-5.

5.

8. The racepinephrine hydrochloride oral solution of claim 5, wherein, The preparation method is as follows: (1) purified water is taken, and hydroxypropyl-β-cyclodextrin is added and stirred under ultrasonic conditions, with the temperature controlled at 40-60°C, to form a stable cavity structure; (2) cyproheptadine hydrochloride is added to the cyclodextrin inclusion liquid prepared in step (1) under stirring conditions, so that it preferentially enters the cyclodextrin cavity to form an inclusion compound; (3) stevioside is added to the inclusion compound formed in step (2), so that the stevioside is directionally adsorbed on the outer cavity surface, thereby forming an inclusion structure; (4) sodium ethyl p-hydroxybenzoate, glycerol, and citric acid-sodium citrate buffer are added, the water content is made up, and stirring is performed until uniform, the pH value is adjusted to the range of 4.5-5.5, and then it is filled, to obtain the product.

9. The racepinephrine hydrochloride oral solution of claim 8, wherein, The ultrasonic conditions are 20-40 kHz low-energy ultrasonic conditions for 60-90 minutes, with the ultrasonic power controlled at 30-80 W and the temperature controlled at 50°C.

10. The racepinephrine hydrochloride oral solution of claim 9, wherein, The ultrasonic conditions are 30 kHz low-energy ultrasonic conditions for 75 minutes, with the ultrasonic power controlled at 50 W and the temperature controlled at 50°C.

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