Oral instant film with high drug loading capacity

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an oral instant film with high drug loading capacity. The oral instant film agent comprises the following components: an active component, a film-forming material, a plasticizer, a coloring agent and a flavoring agent. The film-forming material is preferably combined with hydroxypropyl methylcellulose E15 and xanthan gum, so that the high drug loading capacity of the oral cavity instant film agent is ensured. Film-forming materials including hydroxypropyl methylcellulose E15 and xanthan gum are combined and compounded with a plasticizer polyethylene glycol 400, and sucralose is adopted as a flavoring agent, so that the stability of the oral instant film agent is ensured. The oral cavity instant film is good in appearance property, moderate in flexibility, good in taste, high in drug loading capacity, good in stability, low in cost, easy to operate, free of heating and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to providing an oral fast-dissolving film with a high drug loading. Background Art

[0002] Influenza (flu for short) is an acute respiratory infection caused by influenza virus. It is also a highly contagious and fast-spreading disease. It is mainly transmitted through droplets in the air, contact between people or contact with contaminated objects. Typical clinical symptoms are: sudden high fever, body pain, significant fatigue and mild respiratory symptoms. Generally, autumn and winter are its peak seasons, and the complications and deaths caused are very serious. The disease is caused by influenza virus and can be divided into three types: A, B, and C. Type A virus often undergoes antigenic mutations, is highly contagious, spreads rapidly, and is very likely to become a large-scale epidemic. Type A H1N1 is also a type A. The disease is self-limiting, but it is prone to serious complications such as pneumonia and death in infants, the elderly and patients with underlying cardiopulmonary diseases.

[0003] According to market research, the current antiviral drugs for influenza treatment mainly include oseltamivir phosphate, zanamivir, peramivir, mabaloxavir, arbidol, amantadine, rimantadine and other drugs. The dosage forms of the drugs on the market are mainly tablets, capsules, suspensions, granules, etc. The above dosage forms are inconvenient for children, the elderly and patients with dysphagia to take. Therefore, there is an urgent need for a new dosage form to improve the convenience of patients' medication.

[0004] Oral fast-dissolving films have the following advantages: 1) small size, light weight, convenient to carry, store and transport; 2) accurate dosage, simple preparation process, low cost and stable properties; 3) no need to take with water, just put it on the tip of the tongue to dissolve, can be taken anytime and anywhere; 4) can dissolve quickly after taking, release the drug quickly, and part of the drug can enter the blood system directly through the mucosa to avoid the first-pass effect; 5) has good compliance, especially suitable for children, the elderly and patients with dysphagia, and dissolves immediately in the mouth, which can prevent children from vomiting the drug. However, due to the small size and light weight of oral fast-dissolving films, the drug loading is often small, the shape is soft, and it has certain hygroscopicity, and the demolding performance is poor.

[0005] CN115400098A discloses an orodispersible film of oseltamivir phosphate and a preparation method thereof. Polyvinyl alcohol is used as the film-forming material. Polyvinyl alcohol has a sticky feeling when dissolved in the mouth and is easy to agglomerate. Patient compliance is poor. When insoluble excipients are added, if the film area is large, it is easy to stick to the oral cavity during the dissolution process, which is not conducive to infants and young children taking it. In addition, due to the solubility characteristics of polyvinyl alcohol, heating treatment is required during the preparation process, and the preparation process is complicated.

[0006] In summary, the present application aims to provide an oral fast-dissolving film with a simple preparation process, good appearance, easy dissolution in the mouth without stickiness or greasy feeling, sweet taste, high drug loading, good stability, low cost, no need for heating, and suitable for industrial production. Summary of the invention

[0007] In view of the problems existing in the prior art, the object of the present invention is to provide an oral fast-dissolving film with high drug loading. To achieve this object of the invention, the technical solution adopted by the present invention is:

[0008] The invention discloses an oral fast-dissolving film with high drug loading. The oral fast-dissolving film comprises the following components: 20.0-50.0wt% of active ingredients, 20.0-50.0wt% of film-forming materials, 10.0-30.0wt% of plasticizers, 5.0-15.0wt% of flavoring agents and 0.5-5.0wt% of colorants.

[0009] Furthermore, the active ingredient is selected from one or a mixture of oseltamivir phosphate, zanamivir, peramivir, mabaloxavir, arbidol, amantadine, and rimantadine.

[0010] Furthermore, the film-forming material is selected from one or a mixture of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, xanthan gum, hydroxypropyl cellulose, polyvinyl alcohol 5-88, polyvinyl alcohol 17-88; the film-forming material is more preferably a combination of hydroxypropyl methylcellulose E15 and xanthan gum; the mass ratio of the active ingredient to the film-forming material is 1:0.75-1:1.25.

[0011] Furthermore, the plasticizer is selected from one or a mixture of glycerol, polyethylene glycol 400, propylene glycol, propylene alcohol, and sorbitol; the plasticizer is preferably polyethylene glycol 400.

[0012] Furthermore, the flavoring agent is selected from one or a mixture of sucralose, aspartame, acesulfame potassium, and saccharin sodium; preferably sucralose; and the coloring agent is selected from one or a mixture of iron oxides, titanium dioxide, and β-carotene.

[0013] Furthermore, the preparation method of the oral fast-dissolving film comprises the following steps:

[0014] (1) Weigh the active ingredient, film-forming material, plasticizer, flavoring agent, colorant and purified water according to the ratio and set aside;

[0015] (2) adding the active ingredient, colorant and plasticizer into purified water, stirring and wetting them thoroughly, and then homogenizing and emulsifying them. The emulsification parameters are 4.5-6.5 krpm and the emulsification time is 10-20 min to obtain solution B;

[0016] (3) adding a film-forming material to solution B, and continuing the homogenization and emulsification operation, with the emulsification parameters being 5.5-7.5 krpm and the emulsification time being 10-20 min, to obtain solution C;

[0017] (4) Add the remaining auxiliary materials to solution C, start stirring at 500-1300 rpm for 30 min to obtain solution D;

[0018] (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film;

[0019] (6) Cutting and packaging the rolled film to obtain a finished product.

[0020] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0021] 1. The film-forming material is a combination of hydroxypropyl methylcellulose E15 and xanthan gum, which ensures a high drug loading of the preparation. The preparation process is simple, no heating is required, the film-forming effect is good, the mechanical properties are good, and the film dissolves quickly in the mouth without any sticky or sticky feeling.

[0022] 2. During the experiment, the experimenters found that the flavoring agents and film-forming materials have a great influence on the appearance of the film. The film-forming materials hydroxypropyl methylcellulose E15 and xanthan gum are combined with the plasticizer polyethylene glycol 400, and the flavoring agent is sucralose. This can make the orodispersible film preparation have a better appearance and a better taste, and ensure that the orodispersible film is more stable.

[0023] 3. The colorant preferably comprises titanium dioxide and one or more pigment combinations. Titanium dioxide has a light-shielding effect and a coloring effect, which ensures the stability of the film while beautifying the appearance. DETAILED DESCRIPTION

[0024] The present invention is further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description progresses, but it should be understood that the embodiments are only exemplary and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications or replacements all fall within the protection scope of the present invention.

[0025] Example

[0026] Example 1-8 prescription composition ratio (unit: %):

[0027]

[0028] Comparative Example

[0029] Comparative Examples 1-10 Prescription composition ratio (unit: %):

[0030]

[0031]

[0032] Comparative Examples 11-17 Prescription Composition Ratio (Unit: %):

[0033]

[0034] The preparation method is as follows:

[0035] (1) weighing the active ingredient, film-forming material, plasticizer, flavoring agent, colorant and purified water according to the ratio and setting aside; (2) adding the active ingredient, colorant and plasticizer into purified water, stirring and wetting them thoroughly, and then homogenizing and emulsifying them, with the emulsification parameters being 4.5-6.5 krpm and the emulsification time being 10-20 min, to obtain solution B.

[0036] (3) adding a film-forming material to solution B, and continuing the homogenization and emulsification operation, with the emulsification parameters being 5.5-7.5 krpm and the emulsification time being 10-20 min, to obtain solution C;

[0037] (4) Add the remaining auxiliary materials to solution C, start stirring at 500-1300 rpm for 30 min to obtain solution D;

[0038] (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film;

[0039] (6) Cutting and packaging the rolled film to obtain a finished product.

[0040] Experimental Results

[0041] 1. Appearance and taste

[0042]

[0043] Comparative Examples 2-9 and 13-14 were not tested for taste due to poor appearance or failure to form films. Comparative Example 14 was deaerated before coating, but dense bubbles were generated during the drying process. Comparative Examples 11-12 used sodium saccharin as a flavoring agent, and the film had a good appearance, but when used in the same amount as sucralose, the sweetness was not enough and the film tasted bitter.

[0044] 2. Mechanical properties test results

[0045] Example

[0046]

[0047] Comparative Example

[0048]

[0049] In Comparative Examples 9 and 16, the ratio of drug loading to film-forming material is less than 0.75:1, and film formation is impossible, and conventional tests such as taste, folding resistance and tensile strength are not performed. In Comparative Examples 10 and 17, the ratio of drug loading to film-forming material is greater than 1.25:1. Under the condition of meeting the 45mg specification, the film size is relatively large (the maximum thickness of the oral dissolving film on the market is the Japanese sildenafil citrate oral dissolving film, which is about 0.2mm thick. In order to consider the process compliance, the development thickness is not easy to exceed 0.2mm), which does not meet the size of pediatric medication, and the time limit for dissolving in the mouth is relatively long, which reduces the patient's compliance.

[0050] In Examples 1-8, the folding resistance and breaking strength can meet the requirements of industrial production, the taste is good, and the drug loading can meet the specifications of 50 mg and above. In summary, when the drug loading and film-forming material ratio is within the range of 0.75:1 to 1.25:1, the film properties, size, taste, folding resistance and breaking strength are good.

[0051] 3. Stability test results

[0052] Accelerated test results (50±2°C / 75±5%RH) of Comparative Examples 1-7, 11-15 and Example 1-3:

[0053]

[0054]

[0055] The stability results of Comparative Example 1 and Example 1 show that when the film-forming materials are hydroxypropyl methylcellulose and xanthan gum and the plasticizer is glycerol, the known impurities and unknown impurities increase faster and are more unstable than those in the orodispersible film preparation prepared using polyethylene glycol 400 as the plasticizer.

[0056] The stability results of Comparative Examples 2-6 and Example 1 show that when a single film-forming material is used as the film-forming material, the known impurities and unknown impurities grow faster and are more unstable compared to when the film-forming material is hydroxypropyl methylcellulose and xanthan gum; the impurity growth in Comparative Example 7 is relatively slow, but the film properties are poor.

[0057] The stability results of Comparative Examples 11-14 and Examples 1-3 show that, on the basis of satisfying the property conditions, sucralose has good stability as a flavoring agent, and carrot pigment and yellow iron oxide pigment have no obvious effect on the stability.

[0058] The stability results of Comparative Example 15 and Example 1 show that without adding titanium dioxide, the stability is poor.

[0059] Therefore, the film-forming materials are selected as hydroxypropyl methylcellulose and xanthan gum, and the plasticizer is selected as polyethylene glycol 400, which are compounded in a certain proportion, the flavoring agent is sucralose, and the colorant contains titanium dioxide to ensure that the properties of the oseltamivir phosphate orosoluble film preparation are good and the quality is more stable.

[0060] The present invention uses the above-mentioned embodiments to illustrate the oral fast-dissolving film and the preparation method thereof, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. Provide an oral fast-dissolving film with high drug loading, characterized in that: The oral fast-dissolving film comprises the following components: 20.0-50.0 wt % of active ingredients, 20.0-50.0 wt % of film-forming materials, 10.0-30.0 wt % of plasticizers, 5.0-15.0 wt % of flavoring agents, and 0.5-5.0 wt % of colorants.

2. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that The active ingredient is selected from one or a mixture of oseltamivir phosphate, zanamivir, peramivir, mabaloxavir, arbidol, amantadine, and rimantadine.

3. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that The film-forming material is selected from one or a mixture of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, xanthan gum, hydroxypropyl cellulose, polyvinyl alcohol 5-88, polyvinyl alcohol 17-88.

4. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that The film-forming material is a combination of hypromellose E15 and xanthan gum.

5. The oral fast-dissolving film according to claim 4, characterized in that: The mass ratio of the active ingredient to the film-forming material is 1:0.75-1:1.

25.

6. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that The plasticizer is selected from one or a mixture of glycerol, polyethylene glycol 400, propylene glycol, propylene alcohol, and sorbitol.

7. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that The plasticizer is polyethylene glycol 400.

8. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that: The flavor corrector is selected from sucralose, aspartame, acesulfame potassium, saccharin sodium or a mixture of several of them.

9. The oral fast-dissolving film with high drug loading according to claim 1, characterized in that: The flavoring agent is sucralose; the coloring agent is selected from one or a mixture of iron oxides, titanium dioxide, and beta-carotene pigment.

10. The method for preparing an orally fast dissolving film with high drug loading according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) Weigh the active ingredient, film-forming material, plasticizer, flavoring agent, colorant and purified water according to the ratio and set aside; (2) adding the active ingredient, colorant and plasticizer into purified water, stirring and wetting them thoroughly, and then homogenizing and emulsifying them. The emulsification parameters are 4.5-6.5 krpm and the emulsification time is 10-20 min to obtain solution B; (3) adding a film-forming material to solution B, and continuing the homogenization and emulsification operation, with the emulsification parameters being 5.5-7.5 krpm and the emulsification time being 10-20 min, to obtain solution C; (4) Add the remaining auxiliary materials to solution C, start stirring at 500-1300 rpm for 30 min to obtain solution D; (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film; (6) Cutting and packaging the rolled film to obtain a finished product.

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