Lurasidone hydrochloride oral instant film agent and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lurasidone hydrochloride oral instant film agent and a preparation method thereof. The oral instant film agent comprises the following components: an active component, a film-forming material, a plasticizer, a flavoring agent and a pigment. Wherein a film-forming material is preferably a combination of hydroxypropyl methylcellulose E15 and xanthan gum, so that the whole film-forming system has relatively high drug loading capacity; neotame is preferably selected as the flavoring agent, so that the mouth feel of the oral instant film is improved, and meanwhile, the film agent is ensured to have good mechanical properties. Moreover, the oral instant film can be rapidly disintegrated and dissolved in the oral cavity, is high in drug release speed, can rapidly take effect, is beneficial to improving the medication compliance of patients, especially children patients and elderly patients, is convenient to take, and solves the problem that the oral instant film cannot be taken in time under the condition of no water.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a lurasidone hydrochloride oral fast-dissolving film and a preparation method thereof. Background Art

[0002] Schizophrenia is a group of chronic diseases with unknown etiology. It usually develops slowly or subacutely in young adults. Clinically, it often manifests as a syndrome with different symptoms, involving multiple disorders of perception, thinking, emotion, behavior, and incoordination of mental activities. Patients are generally conscious and have basically normal intelligence, but some patients will experience cognitive impairment during the course of the disease. The course of the disease is generally prolonged, with repeated attacks, aggravation, or deterioration, but some patients can remain cured or basically cured after drug treatment and psychotherapy.

[0003] Lurasidone is an atypical antipsychotic drug that belongs to the chemical class of benzimidazole derivatives. It has antagonistic activity on dopamine 2 (D2) and 5-hydroxytryptamine (5-HT) 2A receptors. Lurasidone hydrochloride (trade name LATUDA) is a new dual-action antipsychotic drug developed by Sunovion Pharmaceuticals Inc. It has significant efficacy on both positive and negative symptoms of patients with psychosis.

[0004] The dosage form of lurasidone hydrochloride on the market is mainly tablets, which are inconvenient to take and have poor compliance for children and elderly patients with difficulty swallowing. In addition, patients in the acute stage of schizophrenia usually refuse to take medicine and are prone to vomiting and hiding medicine. Lurasidone hydrochloride is prepared into an oral fast-dissolving film, which is convenient to carry and take, greatly improves the compliance of patients, and has no risk of clogging the throat. It can be used as an alternative dosage form for traditional oral tablets. The packaging of this product is light and compact, easy to carry, store and transport, not easy to break, and has strong privacy for taking medicine.

[0005] Among them, the combination and proportion of film-forming materials are crucial to the drug loading performance, mechanical properties and taste of the orally dissolving film. This product has a large specification and a high drug loading in a single preparation. The present invention provides a combination and proportion of film-forming materials with high drug loading and good mechanical properties.

[0006] In addition, the orodispersible rapid-release film is rapidly disintegrated in the oral cavity before being swallowed. In order to improve patient compliance, the requirements for the taste are relatively high. The present invention provides a drug combination and ratio with good taste. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a lurasidone hydrochloride oral fast-dissolving film and a preparation method thereof. The present invention provides a lurasidone hydrochloride oral fast-dissolving film that has good taste, dissolves rapidly in the oral cavity, and can take effect quickly by selecting suitable film-forming materials, plasticizers, flavoring agents and colorants, thereby improving the medication compliance of schizophrenia patients.

[0008] Technical Solution

[0009] The invention relates to a lurasidone hydrochloride oral fast-dissolving film preparation, which contains: 25-40 wt % of lurasidone hydrochloride, 30-40 wt % of film-forming material, 15-32 wt % of plasticizer, 1-5 wt % of flavor corrective and 0.1-1 wt % of colorant.

[0010] Furthermore, the film-forming material is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and xanthan gum. The film-forming material is preferably a combination of hydroxypropyl methylcellulose E15 and xanthan gum. The mass ratio of the film-forming material, hydroxypropyl methylcellulose E15 to xanthan gum, is 30:1-15:1.

[0011] Furthermore, the plasticizer is selected from one or more of polyethylene glycol and glycerol.

[0012] Furthermore, the mass ratio of the plasticizer to the film-forming material is 2.5:1-1:1.

[0013] Furthermore, if the flavoring agent is composed of vanilla essence as a base flavoring agent and at least one other flavoring agent, the other flavoring agent is selected from one or more of neotame, sucralose, acesulfame potassium, saccharin sodium, and xylitol, the other flavoring agent is preferably neotame, and the mass ratio of the other flavoring agent to the base flavoring agent is 1.5:1-3.5:1.

[0014] Furthermore, the colorant is selected from one or more of carmine, carotene, indigo, and titanium dioxide.

[0015] Furthermore, the method for preparing the oral fast-dissolving film is characterized by comprising the following steps:

[0016] (1) Weigh the prescribed amount of plasticizer and disperse it in purified water, then weigh the prescribed amount of film-forming material, partially disperse it in 60-70°C purified water to swell, and cool and stir until dissolved;

[0017] (2) dispersing the prescribed amount of API in the solution obtained in step (1), stirring for 3-5 minutes, and then homogenizing the resulting suspension with a homogenizer for 10-15 minutes to make it uniformly dispersed, wherein the API particle size range OD90 is 5.0-10.0 μm;

[0018] (3) adding the remaining amount of the film-forming material to the suspension obtained in step (2), keeping it in a water bath at 60-70° C., cooling it down after swelling, and stirring it until it is dissolved;

[0019] (4) After the solution obtained in step (3) is cooled to room temperature, a prescribed amount of a flavoring agent and a coloring agent are added to the obtained solution and stirred evenly;

[0020] (5) allowing the solution obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at 40-60° C., and removing the film;

[0021] (6) Cut and package the rolled film, and control the weight difference of the film within ±5% to obtain the finished product.

[0022] Beneficial Effects

[0023] The lurasidone hydrochloride oral fast-dissolving film of the present invention has the following advantages:

[0024] (1) The film-forming material uses a combination of hydroxypropyl methylcellulose E15 and xanthan gum, which not only ensures good mechanical properties of the film, but also ensures that the entire film-forming system has a high drug loading, reduces the tablet weight of the film and reduces the cutting size of the film, making it easier for patients to take and improving compliance.

[0025] (2) Lurasidone hydrochloride is bitter and the bitter taste remains in the mouth for a long time. The flavoring agent is selected from vanilla essence as the base flavoring agent and at least one other flavoring agent. The other flavoring agent is preferably neotame, which improves the taste of the oral fast-dissolving film and also ensures the good mechanical properties of the film.

[0026] (3) Compared with ordinary tablets, oral fast-dissolving films are easier to store and transport, and the process does not generate dust, which is beneficial to personnel health protection. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below through examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0028] Example

[0029] The orodispersible film-forming agent comprises the following components: a pharmaceutically active ingredient, a water-soluble polymer film-forming material, a plasticizer, a flavoring agent and a colorant. The pharmaceutically active ingredient is lurasidone hydrochloride, the API particle size range OD90 used is 6.12 μm, and the water-soluble polymer film-forming material is one or more of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, polyvinyl alcohol 5-88, and hydroxypropyl cellulose.

[0030] According to the formula composition in the table below, make a glue with appropriate viscosity, apply it on the PET release film, dry it at 60-90℃, and cut it into 3cm*3.3cm film to get the finished product. The film-forming material is comprehensively evaluated based on appearance, peelability and toughness.

[0031] The prescription compositions of Examples 1-10 are as follows:

[0032]

[0033] Note: Purified water is removed during preparation

[0034] The prescription compositions of Examples 11-12 are as follows:

[0035]

[0036] The process is as follows:

[0037] (1) Weigh the prescribed amount of plasticizer and disperse it in purified water, then weigh the prescribed amount of film-forming material, partially disperse it in 60-70°C purified water to swell, and cool and stir until dissolved;

[0038] (2) dispersing the prescribed amount of API in the solution obtained in step (1), stirring for 3-5 minutes, and then homogenizing the resulting suspension with a homogenizer for 10-15 minutes to make it uniformly dispersed, wherein the API particle size range OD90 is 5.0-10.0 μm;

[0039] (3) adding the remaining amount of the film-forming material to the suspension obtained in step (2), keeping it in a water bath at 60-70° C., cooling it down after swelling, and stirring it until it is dissolved;

[0040] (4) After the solution obtained in step (3) is cooled to room temperature, a prescribed amount of a flavoring agent and a coloring agent are added to the obtained solution and stirred evenly;

[0041] (5) allowing the solution obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at 40 to 60° C., and removing the film;

[0042] (6) Cut and package the rolled film, and control the weight difference of the film within ±5% to obtain the finished product.

[0043] Comparative Example: Lurasidone Hydrochloride Tablets

[0044] Comparative example prescription composition:

[0045]

[0046] Test results:

[0047] Mechanical properties, mouthfeel, and dissolution test results of Examples 1-10:

[0048]

[0049]

[0050] Results of stability tests of Examples 9-12 and Comparative Examples:

[0051] The samples of the present invention and the comparative samples were tested, and the test results of the samples on day 0 and the quality changes of the samples after being placed at 50°C and RH75% for 30 days were examined. The results are shown in the following table:

[0052] Test results of samples on day 0 of the examples and comparative examples

[0053]

[0054] Results of the 30-day accelerated stability test of the samples of the examples and comparative examples

[0055]

[0056] in conclusion:

[0057] It can be seen from Examples 1-8 that when a combination of HPMC E15 and xanthan gum is used, and the mass ratio of HPMC E15 to xanthan gum is 30:1-15:1, the film toughness is stronger, the dissolution time is faster, and the drug loading capacity of the system is higher, which can reduce the tablet weight and cutting size.

[0058] It can be seen from Examples 9-10 that when the mass ratio of plasticizer to film-forming material is 2.5:1-1:1, the toughness, melting time and properties of the film are better.

[0059] It can be seen from Examples 11-12 that when the amount of the flavoring agent is 1.3%-2.3%, the taste is good. Compared with Examples 10 and 11, when neotame is used as a sweetener, the taste is sweeter and the sweetness lasts longer, which can well cover the bitterness caused by the API residue. Neotame is preferably used as a flavoring agent, and the oral dissolving film prepared by the drug film system using neotame has better peelability and toughness than the system using sucralose.

[0060] It can be seen from Examples 9-12 that the content, content uniformity and related substances of the orodispersible film prepared in the examples of the present invention all meet the requirements; the content, content uniformity, dissolution and related substances do not change significantly during the stability period, and the stability is good. The orodispersible film of the present invention dissolves very quickly, reaching more than 90% in 10 minutes, which is consistent with the comparative example. And the accelerated 30-day sample test results show that the content, content uniformity, dissolution and related substances of the orodispersible film prepared in the examples of the present invention do not change significantly during the stability period, and the stability is good.

Claims

1. A lurasidone hydrochloride oral fast-dissolving film, characterized in that: Contains the following prescription ingredients: Lurasidone hydrochloride 25-40wt%, Film-forming material 30-40wt%, Plasticizer 15-32wt%, Flavoring agent 1-5wt%, Colorant 0.1-1wt%.

2. The oral fast-dissolving film according to claim 1, characterized in that The film-forming material is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose and xanthan gum.

3. The oral fast-dissolving film according to claim 1, characterized in that The film-forming material is preferably a combination of hypromellose E15 and xanthan gum.

4. The oral fast-dissolving film according to claim 1, characterized in that The mass ratio of the film-forming material, hydroxypropyl methylcellulose E15 and xanthan gum is 30:1-15:

1.

5. The oral fast-dissolving film according to claim 1, characterized in that The plasticizer is selected from one or more of polyethylene glycol and glycerol; the mass ratio of the plasticizer to the film-forming material is 2.5:1-1:

1.

6. The oral fast-dissolving film according to claim 1, characterized in that The flavoring agent is based on vanilla essence and at least one other flavoring agent, and the other flavoring agent is selected from one or more of neotame, sucralose, acesulfame potassium, saccharin sodium, and xylitol.

7. The oral fast-dissolving film according to claim 6, characterized in that The other flavoring agent is preferably neotame.

8. The oral fast-dissolving film according to claim 6, characterized in that The mass ratio of the other flavoring agents to the basic flavoring agent is 1.5:1-3.5:

1.

9. The oral fast-dissolving film according to claim 1, characterized in that The colorant is selected from one or more of carmine, carotene, indigo and titanium dioxide.

10. The method for preparing the oral fast-dissolving film according to any one of claims 1 to 9, characterized in that: The steps include: (1) Weigh the prescribed amount of plasticizer and disperse it in purified water, then weigh the prescribed amount of film-forming material, partially disperse it in 60-70°C purified water to swell, and cool and stir until dissolved; (2) dispersing the prescribed amount of API in the solution obtained in step (1), stirring for 3-5 minutes, and then homogenizing the resulting suspension with a homogenizer for 10-15 minutes to make it uniformly dispersed, wherein the API particle size range OD90 is 5.0-10.0 μm; (3) adding the remaining amount of the film-forming material to the suspension obtained in step (2), keeping it in a water bath at 60-70° C., cooling it down after swelling, and stirring it until it is dissolved; (4) After the solution obtained in step (3) is cooled to room temperature, a prescribed amount of a flavoring agent and a coloring agent are added to the obtained solution and stirred evenly; (5) allowing the solution obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at 40-60° C., and removing the film; (6) Cut and package the rolled film, and control the weight difference of the film within ±5% to obtain the finished product.

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