Ambroxol hydrochloride oral soluble film and preparation method thereof

Abstract

The invention provides an ambroxol hydrochloride oral soluble film which is prepared from the following components in percentage by weight: 15-20% of ambroxol hydrochloride; 10-20% of a film forming material; 1-5% of a plasticizer; 1-3% of a sweetening agent; 1-5% of a taste masking agent; and 50-70% of a solvent. According to the ambroxol hydrochloride oral soluble film, Kyron T-134 and polacrilin potassium in a specific proportion serve as taste masking agents and have a good combination effect with ambroxol hydrochloride, the taste of the ambroxol hydrochloride oral soluble film can be further improved, bitter taste and tongue numbness are greatly reduced, the ambroxol hydrochloride oral soluble film can be taken by children easily, and patient compliance is enhanced. The ambroxol hydrochloride oral soluble film provided by the invention is high in drug loading capacity, good in mechanical property, uniform in content and good in preparation stability.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to an ambroxol hydrochloride orosoluble film and a preparation method thereof. Background Art

[0002] Ambroxol Hydrochloride is the active metabolite of the expectorant bromhexine and a new generation of mucolytic agent. It can improve expectoration and promote pulmonary surfactant, airway secretion and ciliary movement. It is clinically suitable for young infants and children who have difficulty expectorating.

[0003] Common dosage forms of ambroxol hydrochloride include oral solution, syrup, granules, ordinary tablets, capsules, etc. Oral solution and syrup are often not conducive to children's compliance due to the large dosage. Tablets and capsules are not conducive to widespread use in young children due to children's difficulty in swallowing.

[0004] Orodispersible film is a new type of oral drug delivery system, also known as oral dispersible film, oral dispersible film, oral fast dissolving film, oral fast dissolving film and tongue film, etc. It is a film-like preparation made by processing raw materials and suitable film-forming materials (mostly polymers). When the orodispersible film is placed on the tongue, the film will be immediately moistened by saliva, quickly dissolve in the mouth and release the drug. The released drug can be absorbed through the mucosa or gastrointestinal tract. This drug dosage form is particularly suitable for patients with dysphagia, the elderly, children or bedridden patients, as well as patients who cannot easily obtain water.

[0005] Chinese patent CN113908141A discloses a novel ambroxol composition, which is prepared by a novel hot melt extrusion film drawing technology. The technology does not require the use of plasticizers and disintegrants, and the prepared oral dissolving film has the advantages of high drug loading and good mechanical properties. However, the preparation formula does not add a taste masking agent, and ordinary sweeteners cannot effectively cover the bitter taste and tongue numbness of ambroxol hydrochloride. The preparation has a poor taste, which reduces the patient's compliance. In addition, the technology has high requirements for preparation production equipment, which is not conducive to large-scale promotion and application.

[0006] Chinese patent CN104958280A discloses an ambroxol hydrochloride oral fast-dissolving film and a preparation method thereof, which uses sulfobutyl ether-β-cyclodextrin inclusion technology for taste masking. However, the use of cyclodextrin inclusion cannot completely mask the bitterness and tongue numbness of the drug, and the taste of the preparation can be further improved. In addition, cyclodextrin can easily cause diarrhea, and there are safety risks when used in pediatric patients.

[0007] Chinese patent CN114886874A discloses an oral fast-dissolving film and a preparation method thereof, which includes a drug, a film-forming material, a plasticizer, a flavoring agent and a pigment, and HPMC-E5 and PVA588 are combined as film-forming materials, and the mass ratio of the two is 3:1-4:1; PEG400 and glycerol are combined as plasticizers, and the ratio of the two is 3:1-1:2, the disintegration time of the drug is the shortest, less than 10s, and the drug can be completely dissolved within 5min. However, the formulation does not contain a taste masking agent, and ordinary flavoring agents cannot cover up the bitterness and tongue numbness of ambroxol hydrochloride, which is not conducive to the use of children and reduces the compliance of patients.

[0008] Therefore, it is necessary to develop an ambroxol hydrochloride orodispersible film preparation with good taste, high drug loading and good mechanical properties. Summary of the invention

[0009] In order to solve the problem of poor taste of the ambroxol hydrochloride orodispersible film in the prior art, the present invention provides an ambroxol hydrochloride orodispersible film and a preparation method thereof;

[0010] To achieve the above object, the present invention adopts the following technical scheme:

[0011] An ambroxol hydrochloride orally dissolving film is prepared from the following components in percentage by weight: 15-20% of ambroxol hydrochloride; 10-20% of film-forming material; 1-5% of plasticizer; 1-3% of sweetener; 1-5% of taste-masking agent; and 50-70% of solvent.

[0012] Preferably, an ambroxol hydrochloride orally dissolving film is prepared from the following components in percentage by weight: 16.8% of ambroxol hydrochloride; 16.7% of film-forming material; 2.2% of plasticizer; 1.7% of sweetener; 2.3% of taste-masking agent; and 60.3% of solvent.

[0013] Preferably, the film-forming material is selected from hydroxypropyl cellulose EF and hydroxypropyl methylcellulose E5, wherein the mass ratio of hydroxypropyl cellulose EF to hydroxypropyl methylcellulose E5 is 1:1-2:1.

[0014] More preferably, the mass ratio of hydroxypropyl cellulose EF to hydroxypropyl methylcellulose E5 is 1.5:1.

[0015] Preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol and hexylene glycol.

[0016] More preferably, the plasticizer is polyethylene glycol 400.

[0017] Preferably, the sweetener may be selected from one or more of sucralose, aspartame, trehalose, sucrose, and sorbitol.

[0018] More preferably, the sweetener is sucralose.

[0019] Preferably, the taste masking agent is selected from Kyron T-134 and polyclinic potassium, wherein the mass ratio of Kyron T-134 to polyclinic potassium is 0.5-1:3.

[0020] More preferably, the mass ratio of Kyron T-134 to polyclinic potassium is 1:3.

[0021] Preferably, the solvent is selected from ethanol and purified water, wherein the mass ratio of ethanol to purified water is 8:1.

[0022] The present invention also provides a method for preparing an ambroxol hydrochloride orally soluble film, which comprises the following steps:

[0023] (5) Weigh one-half of the prescribed amount of purified water and ethanol, mix them, add the prescribed amount of ambroxol hydrochloride, stir until completely dissolved, then add the prescribed amount of taste masking agent, stir and disperse, and homogenize at 7000 rpm for 3-4.5 min to obtain solution A.

[0024] (6) Weigh the remaining amount of purified water and ethanol, mix them, add the prescribed amount of film-forming material, stir and dissolve, then add the prescribed amount of plasticizer and sweetener, stir and dissolve, to obtain solution B.

[0025] (7) Solution A and solution B were mixed, stirred and dispersed, homogenized at 7000 rpm for 1.5 min, allowed to stand for 8-12 h, and defoamed to obtain a coating solution.

[0026] (8) Setting the coating height to 0.3-0.5 mm, evenly coating the coating liquid on the high temperature resistant PET tape at a coating rate of 15-25 mm / s, drying at 60° C. for 15 min, and cutting to obtain the ambroxol hydrochloride orally soluble film.

[0027] In summary, the beneficial effects of the present invention are:

[0028] The invention uses Kyron T-134 and polyclinic potassium in a specific ratio as taste masking agents, which can effectively bind free ambroxol hydrochloride, is conducive to further improving the taste of the ambroxol hydrochloride oral dissolving film, greatly reduces the bitter taste and tongue numbness, is conducive to children's taking, and enhances the compliance of patients.

[0029] The ambroxol hydrochloride orally dissolving film provided by the invention has high drug loading, good mechanical properties, uniform content and good preparation stability. DETAILED DESCRIPTION

[0030] The following will be combined with the embodiments of the invention to clearly and completely describe the technical solutions in the embodiments of the invention. Obviously, the described embodiments are only part of the embodiments of the invention, not all of the embodiments. Based on the embodiments of the invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the invention.

[0031] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0032] Example 1

[0033] An ambroxol hydrochloride orodispersible film, each piece of which contains 15 mg of ambroxol hydrochloride, and 1000 pieces of ambroxol hydrochloride orodispersible film are composed of:

[0034]

[0035]

[0036] Preparation process:

[0037] Weigh half of the prescribed amount of purified water and ethanol, mix them, add the prescribed amount of ambroxol hydrochloride, stir until completely dissolved, then add the prescribed amount of Kyron T-134 and polyclinic potassium, stir and disperse, homogenize at 7000 rpm for 3 min, and obtain solution A.

[0038] Weigh the remaining prescribed amount of purified water and ethanol, mix them, add the prescribed amount of hydroxypropyl cellulose EF and hydroxypropyl methylcellulose E5, stir to dissolve, then add the prescribed amount of polyethylene glycol 400 and sucralose, stir to dissolve, to obtain solution B.

[0039] Solution A and solution B were mixed, stirred and dispersed, homogenized at 7000 rpm for 1.5 min, allowed to stand for 10 h, and defoamed to obtain a coating solution.

[0040] The coating height was set to 0.5 mm, and the coating liquid was evenly coated on the high temperature resistant PET tape at a coating rate of 20 mm / s. The film was dried at 60° C. for 15 min and cut into 1.8 cm*2 cm pieces to obtain the ambroxol hydrochloride orally soluble film.

[0041] Example 2-6 Investigation of the mass ratio and dosage of film-forming materials

[0042] An ambroxol hydrochloride orodispersible film, each containing 15 mg of ambroxol hydrochloride, and the formulation of 1000 tablets is as follows:

[0043]

[0044]

[0045] The preparation process is the same as that of Example 1.

[0046] The effects of different film-forming material dosages on the bending times and demolding of the preparations are shown in the following table:

[0047] Example 2 Example 3 Example 4 Example 5 Example 6 Demolding Easy to remove film Easy to remove film Easy to remove film Not easy to remove the film Not easy to remove the film Bending times 2 3 2 / 1

[0048] Hydroxypropyl cellulose EF and Hydroxypropyl methylcellulose E5 are film-forming materials, and their dosage directly affects the physical properties of orally dissolving film preparations. Studies have found that too high or too low a content of hydroxypropyl cellulose EF will affect the viscosity of the coating solution, thereby affecting film removal. When the mass ratio of hydroxypropyl cellulose EF to Hydroxypropyl methylcellulose E5 is within the range of 1:1-2:1, film removal is easy and the orally dissolving film has good mechanical properties and is not easy to break.

[0049] Example 7-12 Investigation of the dosage and mass ratio of taste masking agent

[0050] An ambroxol hydrochloride orodispersible film, each containing 15 mg of ambroxol hydrochloride, and the formulation of 1000 tablets is as follows:

[0051]

[0052] The preparation method is the same as Example 1.

[0053] Comparative Example 1

[0054] Referring to the preparation method of Example 6 in patent CN104958280A, an ambroxol hydrochloride orally soluble film was prepared as comparative example 1.

[0055] Comparative Example 2

[0056] The taste masking agent in the present invention is removed, and the type and amount of sweetener are increased to form an empty bag control group without a taste masking agent. The specific prescription is as follows:

[0057] Prescription composition Comparative Example 2 Ambroxol Hydrochloride 15g Hydroxypropyl Cellulose EF 9g Hydroxypropyl methylcellulose E5 6g Polyethylene glycol 400 2g Sucralose 2.5g Strawberry flavor 1g Ethanol 48g Purified water 6g

[0058] Bitterness measurement and taste evaluation of orodispersible film using electronic tongue

[0059] Take 5 pieces of 15 mg orodispersible films prepared in Examples 7-12, Comparative Examples 1 and 2, place the orodispersible films in 25 ml of artificial saliva, shake for 1 min, and immediately pass through a 0.45 μm aqueous membrane to obtain a filtrate, and measure its bitterness value using an electronic tongue.

[0060] Taste evaluation method:

[0061] Six healthy adults (3 men and 3 women) were selected to place a piece of orodispersible film on the tongue without taking water. The bitterness after the orodispersible film was completely dissolved was recorded. After 30 seconds, the mouth was rinsed and the residual taste after rinsing was recorded. The bitterness value was scored according to the classification in the table below and the average value was calculated.

[0062] The bitterness scoring rules in the taste evaluation are: no bitterness or numbing sensation at all, 0 point; almost no bitterness or numbing sensation, 1 point; a little bitterness or numbing sensation, 2 points; obvious bitterness or numbing sensation, 3 points; very strong bitterness or numbing sensation, 4 points.

[0063] The electronic tongue bitterness values ​​and the oral taste evaluation results of Examples 7-12, Comparative Examples 1 and 2 are shown in the following table:

[0064] sample Electronic tongue bitterness measurement value Average taste evaluation Artificial saliva 0 0 Example 7 1.02 1 Example 8 0.35 0 Example 9 5.45 2 Example 10 8.37 2 Embodiment 11 0.54 0 Example 12 15.10 3 Comparative Example 1 11.48 2.5 Comparative Example 2 23.68 3.3

[0065] The experimental results show that when the dosage ratio of the taste masking agent potassium polyclinic and Kyron T-134 is 3:1-0.5, the taste masking effect is better, and the bitter and numb taste is almost unnoticeable. As the dosage of potassium polyclinic increases, the taste masking effect remains almost unchanged. As the dosage of potassium polyclinic decreases, the taste masking effect decreases. When only Kyron T-134 is used as a taste masking agent, the bitter and numb taste is obvious, which is not conducive to patient compliance.

[0066] Comparative Example 1: The cyclodextrin inclusion technology has a poor taste masking effect, and half of the people still feel that it has a significant bitter and numb feeling. Comparative Example 2: No taste masking agent is included, and the amount of sweetener used is increased, but it still cannot mask the bitterness and tongue numbness of ambroxol hydrochloride, and 2 people evaluate that the bitter and numb feeling is strong. Therefore, the taste masking agent selected by the present invention has a good taste masking effect, which is conducive to improving the compliance of pediatric patients.

[0067] Example 13-14 Solvent dosage investigation

[0068] Ethanol and water are used as solvents in the prescription. Their dosage affects the viscosity of the preparation, thereby affecting the sedimentation risk of the preparation, and thus affecting the content uniformity of the preparation. The effect of proportionally increasing the dosage of ethanol and water on the content uniformity of the preparation was investigated.

[0069] Prescription composition Embodiment 13 Embodiment 14 Ambroxol Hydrochloride 15g 15g Hydroxypropyl Cellulose EF 9g 9g Hydroxypropyl methylcellulose E5 6g 6g Polyethylene glycol 400 2g 2g Sucralose 1.5g 1.5g Polyclinic potassium 1.5g 1.5g KyronT-134 0.5g 0.5g Ethanol 40g 48g Purified water 5g 6g

[0070] The preparation process is the same as that of Example 1.

[0071] Ten orally dissolving films prepared in Example 13 and Example 14 were taken respectively to investigate the effects of different amounts of ethanol and water on the content uniformity of the preparations. The test results are shown in the table below:

[0072] Effect of different solvent dosage on content uniformity of preparations

[0073]

[0074] The experimental results show that when preparing the orodispersible film in Example 13, the viscosity of the drug solution is too large, which is not conducive to uniform mixing of the sample. After increasing the amount of solvent, the content uniformity is qualified, and no obvious sedimentation occurs during degassing and coating after liquid preparation. The content uniformity of the preparation meets the requirements. Therefore, the amount of ethanol used is 48 mg / tablet and the amount of purified water used is 6 mg / tablet.

[0075] Preparation stability study

[0076] The orodissolving film prepared in Example 1 was selected to investigate the stability of the preparation. Ten orodissolving films were taken for accelerated stability test and long-term stability test. The test results are shown in the following table:

[0077] Example 1 Preliminary stability study results

[0078]

[0079] The experimental results show that the stability of the orally dissolving film prepared by the present invention meets the limit requirements.

[0080] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An ambroxol hydrochloride orodispersible film, characterized in that: The invention is prepared from the following components in percentage by weight: 15-20% of ambroxol hydrochloride; 10-20% of film-forming material; 1-5% of plasticizer; 1-3% of sweetener; 1-5% of taste-masking agent; and 50-70% of solvent.

2. A kind of ambroxol hydrochloride orodispersible film according to claim 1, characterized in that, The invention is prepared from the following components in percentage by weight: 16.8% of ambroxol hydrochloride; 16.7% of film-forming material; 2.2% of plasticizer; 1.7% of sweetener; 2.3% of taste-masking agent; and 60.3% of solvent.

3. A kind of ambroxol hydrochloride orodispersible film according to claim 1, characterized in that, The film-forming material is selected from hydroxypropyl cellulose EF and hydroxypropyl methyl cellulose E5, wherein the mass ratio of hydroxypropyl cellulose EF to hydroxypropyl methyl cellulose E5 is 1:1-2:

1.

4. A kind of ambroxol hydrochloride orodispersible film according to claim 3, characterized in that, The mass ratio of the hydroxypropyl cellulose EF to the hydroxypropyl methyl cellulose E5 is 1.5:

1.

5. A kind of ambroxol hydrochloride orodispersible film according to claim 1, characterized in that, The plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol and hexylene glycol.

6. An ambroxol hydrochloride orodispersible film according to claim 1, characterized in that: The sweetener may be selected from one or more of sucralose, aspartame, trehalose, sucrose, and sorbitol.

7. An ambroxol hydrochloride orodispersible film according to claim 1, characterized in that: The taste masking agent is selected from Kyron T-134 and polyclinic potassium, wherein the mass ratio of Kyron T-134 to polyclinic potassium is 0.5-1:

3.

8. An ambroxol hydrochloride orodispersible film according to claim 7, characterized in that: The mass ratio of Kyron T-134 to polyclinic potassium is 1:

3.

9. The ambroxol hydrochloride orodispersible film according to claim 1, characterized in that: The solvent is selected from ethanol and purified water, wherein the mass ratio of ethanol to purified water is 8:

1.

10. The method for preparing the ambroxol hydrochloride oral dissolving film according to claim 1, comprising the steps of: (1) Weigh one-half of the prescribed amount of purified water and ethanol, mix them, add the prescribed amount of ambroxol hydrochloride, stir until completely dissolved, then add the prescribed amount of taste masking agent, stir and disperse, and homogenize at 7000 rpm for 3-4.5 min to obtain solution A. (2) Weigh the remaining amount of purified water and ethanol, mix them, add the prescribed amount of film-forming material, stir and dissolve, then add the prescribed amount of plasticizer and sweetener, stir and dissolve, to obtain solution B. (3) Solution A and solution B were mixed, stirred and dispersed, homogenized at 7000 rpm for 1.5 min, allowed to stand for 8-12 h, and defoamed to obtain a coating solution. (4) Setting the coating height to 0.3-0.5 mm, evenly coating the coating liquid on the high temperature resistant PET tape at a coating rate of 15-25 mm / s, drying at 60° C. for 15 min, and cutting to obtain the ambroxol hydrochloride orally soluble film.

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