Pinefibrate oral dissolving film agent and preparation method thereof

Abstract

The invention relates to the technical field of medicine preparation, in particular to a baltefibrate oral-soluble film agent and a preparation method thereof, and the baltefibrate oral-soluble film agent can achieve ideal dissolution speed and bioavailability equivalent to tablets in an oral cavity by controlling particle size distribution of raw material medicines in the baltefibrate oral-soluble film agent and dissolving baltefibrate through polyvinylpyrrolidone aqueous dispersion. According to the invention, the characteristic of good dissolution effect can be realized without additionally adding a pH regulator, and rapid disintegration and dissolution can be realized without additionally adding water in the oral cavity. The preparation method of the Pengfibrate oral soluble film is simple and easy to operate, and is suitable for modern industrial mass production, required production equipment is conventional equipment, the cost is saved, and the production possibility is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and more specifically, relates to a Pemabet orodispersible film-forming agent and a preparation method thereof. Background Art

[0002] Fibrates are important drugs for lowering triglycerides. They lower triglycerides and increase high-density lipoprotein cholesterol by activating peroxisome proliferator-activated receptors (PPARα). Pemabate is a new type of highly selective PPRA-α agonist that selectively binds to and regulates the expression of target genes, inhibits apolipoprotein CIII (apoC-III) and angiopoietin-like protein 3 (ANGPTL3), and increases lipase (LPL), thereby reducing plasma triglyceride levels and increasing high-density lipoprotein (HDL) cholesterol levels. Pemabate is almost insoluble in water, but its solubility increases in alkaline solutions. Its structural formula is as follows:

[0003]

[0004] Compared with other PPRA-α agonist drugs, Pemabet has a stronger lipid-lowering effect, but the content of the main ingredient of Pemabet in the preparation is low, so it is necessary to ensure that its content uniformity meets the requirements. In addition, Pemabet has poor water solubility, which leads to low solubility after it is made into an oral solid preparation, which in turn affects its bioavailability in the body.

[0005] Chinese patents CN110831591 and CN110809469 only provide a pharmaceutical composition that improves the uniformity of the content of Pemabet, but do not provide a complete invention for preparing a Pemabet preparation.

[0006] Chinese patent CN118490655 discloses a Pemabet tablet and its preparation method. The mixing of raw materials and auxiliary materials requires the use of specific vibration equipment, the granulation process requires specific spraying equipment, and then tableting and coating are performed to obtain qualified tablets. However, this process has high requirements on equipment, is difficult to scale up, is difficult to industrialize, and has poor practicality.

[0007] The pharmaceutical preparations of Pemabet disclosed in the prior art are mainly oral tablets. Current research also focuses on improving the uniformity of tablet content. However, ordinary tablets have poor compliance for bedridden patients and patients with dysphagia.

[0008] As a new oral drug delivery system, the orodispersible film belongs to the film dosage form among drug dosage forms and is an oral solid rapid-release preparation. The orodispersible film is easy to carry and use. It can dissolve quickly on the tongue and be swallowed with normal swallowing movements. It not only enables convenient, fast and accurate medication when it is inconvenient to drink water or there is no drinking water supply, but also, compared with common boxed or bottled medicines, it is smaller in size and easier to carry, which can better meet the needs of fast-paced, high-pressure urban people. It is especially suitable for the elderly and critically ill patients, and improves patient compliance.

[0009] Therefore, it is necessary to develop a Pemabet orosoluble film preparation that has high content uniformity, good dissolution effect, rapid onset of action, rapid disintegration in the oral cavity without the need for additional water, and is suitable for large-scale modern industrial production.

[0010] Some studies have reported that β-cyclodextrin inclusion is used in injections to achieve the purpose of solubilization. However, the drug loading capacity of the orodispersible film is limited, and this method cannot meet the required amount of the drug. Therefore, in the preparation process of the orodispersible film, choosing a suitable solubilizer to promote the complete dissolution of Pemabet is a technical problem that needs to be solved urgently. Summary of the invention

[0011] The present invention provides a permabate orodispersible film with improved drug uniformity and solubility. The present invention controls the particle size distribution of the raw material drug in the permabate orodispersible film and dissolves the permabate through a polyvinylpyrrolidone aqueous dispersion, so that the permabate can achieve an ideal dissolution rate in the oral cavity and a bioavailability equivalent to that of a tablet.

[0012] In order to increase the specific surface area as much as possible so that the drug can be dissolved quickly, the Pemabet oral dissolving film of the present invention comprises fine particles (D 90 :10μm) of Pemabet or a pharmaceutically acceptable salt thereof. Wherein "D 90 " means that 90% of the particles have a particle size below the stated value. For example, D 90 : 10 μm means that 90% of the particles have a particle size below 10 μm.

[0013] On the one hand, the present invention provides a Pemabet orodispersible film, wherein the Pemabet orodispersible film comprises, by weight percentage, 0.083% Pemabet, 20-50% film former, 20-40% solubilizer, 5-15% plasticizer, 5-15% disintegrant, 2-6% flavoring agent, and the sum of the percentages of each component is 100%; the D of the Pemabet raw material is 90 The particle size is ≤10μm; the pH of the Pemabet orosoluble film is between 6.8-10.0.

[0014] The present invention discloses a Pemabet orodissolving film, which comprises the following components in weight percentage: 0.083% Pemabet, 20-50% film former, 20-40% solubilizer, 5-15% plasticizer, 5-15% disintegrant and 2-6% flavor corrective.

[0015] Furthermore, the D of the Pemabet API 90 The particle size is ≤10 μm; the pH value of the Pemabet orosoluble film is 6.8-10.0.

[0016] Furthermore, the film-forming agent is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, xanthan gum, pectin, polyethylene oxide, and polyvinyl pyrrolidone aqueous dispersion.

[0017] Furthermore, the solubilizing agent is selected from at least one of poloxamer, Tween 80, sodium lauryl sulfate, vitamin E succinate and meglumine.

[0018] Furthermore, the plasticizer is selected from at least one of glycerol, polyvinyl alcohol and propylene glycol.

[0019] Furthermore, the disintegrant is selected from at least one of mannitol, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium and sodium carboxymethyl starch.

[0020] Furthermore, the Pemabet orosoluble film comprises, by weight, 0.083% Pemabet, 30-50% film former, 30-40% solubilizer, 10-15% plasticizer, 10-15% disintegrant and 4-6% flavoring agent.

[0021] Furthermore, the Pemabet orodispersible film further comprises a flavoring agent; the flavoring agent is a sweetener and a fragrance;

[0022] The sweetener is selected from at least one of glucose, xylitol, maltitol, neotame, saccharin sodium, aspartame and sodium cyclamate;

[0023] The aromatic agent is selected from at least one of peppermint oil, menthol, tea tree oil, menthol and clove oil.

[0024] Furthermore, the preparation method of the Pemabet orodispersible film is as follows:

[0025] (1) grinding the permabate starting material by a bead milling process until 90% of the permabate has a particle size of ≤10.0 μm;

[0026] (2) dissolving polyvinyl pyrrolidone and sodium lauryl sulfate to obtain a polyvinyl pyrrolidone aqueous dispersion;

[0027] (3) adding the Pemabet obtained in step (1) and a solubilizer to the polyvinyl pyrrolidone aqueous dispersion and mixing evenly, then adding a film-forming agent, a disintegrant, a plasticizer and a sweetener and mixing evenly to obtain a glue solution; wherein the pH of the glue solution is 6.8-10.0;

[0028] (4) The aromatic agent is dissolved in ethanol and then added to the glue solution, which is allowed to stand in a vacuum state to defoam. The orodispersible film coating and drying machine is used to coat, dry, and cut to obtain the Pemabet orodispersible film.

[0029] A pharmaceutical composition of the present invention comprises the Pemabet orosoluble film according to any one of claims 1 to 6.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The present invention provides a Pemabet orodissolving film, which has the characteristics of good dissolution effect without the need for additional addition of a pH regulator, and can achieve rapid disintegration and dissolution in the oral cavity without the need for additional water. It overcomes the shortcomings of ordinary tablets, such as poor patient compliance, and has the advantages of stable quality, high bioavailability, and enhanced efficacy. The preparation method of the Pemabet orodissolving film of the present invention is simple and easy to operate, suitable for large-scale modern industrial production, and the required production equipment is conventional equipment, which saves costs and improves the possibility of production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is a cumulative dissolution curve of the Pemabet orodispersible film described in Examples 1-6;

[0033] Figure 2 This is a cumulative dissolution curve of the Pemabet orosoluble film described in Examples 1-5. DETAILED DESCRIPTION

[0034] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0035] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0036] 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.

[0037] The prescription composition of the Pemabet orodispersible film of the embodiment of the present invention is as follows:

[0038] Table 1

[0039]

[0040] Table 2

[0041]

[0042]

[0043] Preparation process:

[0044] (1) grinding the permabate starting material by a bead milling process until 90% of the permabate has a particle size of ≤10.0 μm; the spindle speed of the bead milling process is ≥2500 rpm, and the number of grinding cycles is ≥4 times;

[0045] (2) dissolving polyvinyl pyrrolidone and sodium lauryl sulfate to obtain a polyvinyl pyrrolidone aqueous dispersion;

[0046] (3) adding the Pemabet obtained in step (1) and a solubilizer to the polyvinyl pyrrolidone aqueous dispersion, and then adding a film-forming agent, a disintegrant, a plasticizer and a sweetener, and mixing to obtain a glue solution;

[0047] Dissolve the aromatic in ethanol and add it to the glue solution, let it stand for vacuum defoaming, use a mouth-soluble film coating and drying machine to coat, dry, and cut to obtain the Pemabet mouth-soluble film;

[0048] Test Example 1

[0049] Appearance evaluation

[0050] Appearance is evaluated by flexibility, smoothness, and uniformity of the film. Flexibility: Inspects the difficulty of film removal and the damage caused by film removal. The easier it is to remove the film and the higher the score is without damage during the film removal process; Smoothness: Inspects the presence of bubbles and the number of small bumps. The higher the score is with no small bumps and bubbles; Uniformity of the film: Inspects whether the thickness of each film cut is consistent and the weight difference. The higher the score is with consistent thickness or small weight difference. The thickness is measured by a digital micrometer (range 0-25mm, resolution 0.001mm).

[0051] The appearance scores of the samples of Examples 1-6 and Comparative Examples 1-5 were evaluated and statistically analyzed according to the following standards.

[0052] The evaluation criteria are shown in Table 3:

[0053] Table 3 Appearance evaluation basis and corresponding scores

[0054]

[0055]

[0056] The experimental results are shown in Table 4:

[0057] Table 4 Appearance evaluation results of each embodiment and comparative example

[0058]

[0059]

[0060] Test Example 2

[0061] Tensile strength and elongation at break tests

[0062] Take a piece of this product and use an intelligent film tensile tester to measure the tensile strength and elongation at break. The results are shown in Table 5.

[0063] Table 5 Test results of tensile strength and elongation at break of various embodiments and comparative examples

[0064]

[0065]

[0066] Test Example 3

[0067] Melting Time, Content Uniformity and Cumulative Dissolution Testing

[0068] Dissolution time: Check according to the method under the disintegration time limit test method for tablets (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0921); Content uniformity: Check according to (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512 High Performance Liquid Chromatography); Cumulative dissolution: Check according to (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method). The results are shown in Table 6.

[0069]

[0070] It can be seen from Table 6 that the cumulative dissolution of Pemabet in the orosoluble film provided by the present invention can be ≥90% within 30 minutes, and the preparation prepared by using polyvinyl pyrrolidone aqueous dispersion and adding solubilizer sodium dodecyl sulfate has high content uniformity, good dissolution effect, uniform appearance and good film flexibility.

[0071] Sodium dodecyl sulfate plays a major role in solubilization in this application, and the solution is alkaline, which has a better effect on promoting the dissolution of Pemabet. The present invention solves the solubility problem of Pemabet beyond expectations by selecting a suitable solubilizing agent to dissolve and disperse the drug, and then makes an orally soluble film with the film-forming agent of the present invention. The prepared film has a smooth surface, no particles, and a good taste.

[0072] It can be seen from the above embodiments and comparative examples that the Pemabet orodispersible film with a specific prescription of the present invention has qualified appearance, good film physical properties, rapid disintegration, high content uniformity, and good dissolution effect after testing. In addition, the preparation method is simple and easy to operate, saves energy, and is suitable for large-scale industrial production.

[0073] The above is an implementation scheme of the present invention designed for a case. It should be pointed out that for ordinary technicians in this technical field, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the scope of protection of the present invention.

Claims

1. A Pemabet orodispersible film, characterized in that: The Pemabet orodispersible film comprises the following components in percentage by weight: 0.083% Pemabet, 20-50% film former, 20-40% solubilizer, 5-15% plasticizer, 5-15% disintegrant and 2-6% flavor corrector.

2. The Pemabet orosoluble film according to claim 1, characterized in that: The D of the Pemabet API 90 The particle size is ≤10 μm; the pH value of the Pemabet orosoluble film is 6.8-10.

0.

3. The Pemabet orosoluble film according to claim 1, characterized in that: The film-forming agent is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, xanthan gum, pectin, polyethylene oxide, and polyvinyl pyrrolidone aqueous dispersion.

4. The Pemabet orosoluble film according to claim 1, characterized in that: The solubilizing agent is selected from at least one of poloxamer, Tween 80, sodium lauryl sulfate, vitamin E succinate and meglumine.

5. The Pemabet orosoluble film according to claim 1, characterized in that: The plasticizer is selected from at least one of glycerol, polyvinyl alcohol and propylene glycol.

6. The Pemabet orodispersible film according to claim 1, characterized in that: The disintegrant is selected from at least one of mannitol, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium and sodium carboxymethyl starch.

7. The Pemabet orodispersible film according to any one of claims 1 to 6, characterized in that: The Pemabet orodispersible film comprises, by weight, 0.083% of Pemabet, 30-50% of a film former, 30-40% of a solubilizer, 10-15% of a plasticizer, 10-15% of a disintegrant and 4-6% of a flavoring agent.

8. The Pemabet orodispersible film according to any one of claims 1 to 6, characterized in that: The Pemabet orodispersible film further comprises a flavoring agent; the flavoring agent is a sweetener and a fragrance; The sweetener is selected from at least one of glucose, xylitol, maltitol, neotame, saccharin sodium, aspartame and sodium cyclamate; The aromatic agent is selected from at least one of peppermint oil, menthol, tea tree oil, menthol and clove oil.

9. The method for preparing the Permabet orodispersible film according to any one of claims 1 to 6, characterized in that: The preparation method of Pemabet orodispersible film is as follows: (1) grinding the permabate starting material by a bead milling process until 90% of the permabate has a particle size of ≤10.0 μm; (2) dissolving polyvinyl pyrrolidone and sodium lauryl sulfate to obtain a polyvinyl pyrrolidone aqueous dispersion; (3) adding the Pemabet obtained in step (1) and a solubilizer to the polyvinyl pyrrolidone aqueous dispersion and mixing evenly, then adding a film-forming agent, a disintegrant, a plasticizer and a sweetener and mixing evenly to obtain a glue solution; wherein the pH of the glue solution is 6.8-10.0; (4) The aromatic agent is dissolved in ethanol and then added to the glue solution, which is allowed to stand in a vacuum state to defoam. The orodispersible film coating and drying machine is used to coat, dry, and cut to obtain the Pemabet orodispersible film.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the Pemabet orosoluble film according to any one of claims 1 to 6.

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