Application of sustained-release film-coated premix in preparation of pneilol hydrochloride sustained-release tablet

Abstract

The invention provides an application of a sustained-release film coating premix in preparation of a pneilol hydrochloride sustained-release tablet. The sustained-release film coating premix comprises the following components in parts by weight: 20-25 parts by weight of ethyl cellulose; 40-50 parts by weight of an acrylic resin; 5 to 15 parts by weight of hydroxypropyl methyl cellulose; 10 to 20 parts by weight of PEG400 (polyethylene glycol 400); 8 to 12 parts by weight of lactose; and 5-10 parts by weight of an anti-sticking agent. The provided slow-release film-coated premix can be used for preparing the pneilol hydrochloride sustained-release tablet and can be slowly released.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to the application of a sustained-release film coating premix in the preparation of propranolol hydrochloride sustained-release tablets. Background Art

[0002] Sustained-release preparations refer to preparations that can continuously release drugs for a long time after administration to achieve a long-acting effect. Sustained-release preparations refer to oral drugs that are slowly and non-constantly released in a specified solvent as required, and the number of daily drug administrations is at least reduced by one or the dosing interval is extended compared with the corresponding conventional preparations.

[0003] Propranolol hydrochloride is a β-blocker, mainly used for the treatment of cardiovascular diseases such as hypertension, angina pectoris, and arrhythmia. However, due to its short half-life (3 - 6 hours), it needs to be administered multiple times a day clinically, so there will be problems such as large fluctuations in blood drug concentration (peak-to-valley ratio > 3) and poor patient compliance. Summary of the Invention

[0004] The present invention aims to solve at least one of the technical problems in the related art to some extent. The film coating technology realizes drug sustained release by regulating the permeability of the coating film, and has advantages such as high process stability and strong controllability of release behavior compared with matrix-type sustained-release tablets. The present invention provides a sustained-release film coating premix, which can be used for the preparation of propranolol hydrochloride sustained-release tablets.

[0005] Specifically, the present invention provides the following technical solutions:

[0006] The first aspect of the present invention provides the use of a sustained-release film coating premix in the preparation of propranolol hydrochloride sustained-release tablets, and the sustained-release film coating premix includes, by weight:

[0007] 20 - 25 parts by weight of ethylcellulose;

[0008] 40 - 50 parts by weight of acrylic resin;

[0009] 5 - 15 parts by weight of hypromellose;

[0010] 10 - 20 parts by weight of PEG400;

[0011] 8 - 12 parts by weight of lactose,

[0012] 5 - 10 parts by weight of anti-adhesive agent.

[0013] The provided sustained-release film coating premix includes ethyl cellulose, acrylic resin, hydroxypropyl methylcellulose, PEG400, lactose, and an anti-adhesive agent. Among them, ethyl cellulose serves as a hydrophobic skeleton to delay drug release, and HPMC serves as a hydrophilic gel skeleton to form a diffusion barrier through swelling. Acrylic resin can be used to regulate pH-dependent release, especially suitable for intestinal sustained release. PEG400, as a plasticizer, can significantly improve the crystallinity of the composite film, enhance the denseness and processing performance of the film compared with other plasticizers, and can help the stable release of the sustained-release tablets. Moreover, PEG400 has a moderate molecular weight, which can not only be used as a plasticizer to regulate the film properties but also as a pore-forming agent or penetration enhancer. The prepared propranolol hydrochloride sustained-release tablets can delay release.

[0014] According to an embodiment of the present invention, the use of the above-provided sustained-release film coating premix in the preparation of propranolol hydrochloride sustained-release tablets may further include the following technical features:

[0015] According to an embodiment of the present invention, the sustained-release film coating premix, by weight, includes:

[0016] 20-25 parts by weight of ethyl cellulose;

[0017] 40-45 parts by weight of acrylic resin;

[0018] 8-10 parts by weight of hydroxypropyl methylcellulose;

[0019] 12-18 parts by weight of PEG400;

[0020] 8-10 parts by weight of lactose;

[0021] 5-10 parts by weight of anti-adhesive agent.

[0022] According to an embodiment of the present invention, the sustained-release film coating premix, by weight, includes:

[0023] 25 parts by weight of ethyl cellulose;

[0024] 40 parts by weight of acrylic resin;

[0025] 10 parts by weight of hydroxypropyl methylcellulose;

[0026] 15 parts by weight of PEG400;

[0027] 8 parts by weight of lactose,

[0028] 5 parts by weight of talc,

[0029] 5 parts by weight of silicon dioxide.

[0030] According to an embodiment of the present invention, the anti-sticking agent is talcum powder or silicon dioxide.

[0031] According to an embodiment of the present invention, the acrylic resin is Eudragit RL100.

[0032] The second aspect of the present invention provides a propranolol hydrochloride sustained-release tablet, comprising: 92 to 94 parts by weight of a propranolol hydrochloride tablet core and 6 to 8 parts by weight of a sustained-release film coating premix, and the sustained-release film coating premix forms a coating on the surface of the propranolol hydrochloride tablet core;

[0033] The sustained-release film coating premix, by weight, comprises:

[0034] 20 - 25 parts by weight of ethylcellulose;

[0035] 40 - 50 parts by weight of acrylic resin;

[0036] 5 - 15 parts by weight of hydroxypropyl methylcellulose;

[0037] 10 - 20 parts by weight of PEG400;

[0038] 8 - 12 parts by weight of lactose,

[0039] 5 - 10 parts by weight of anti-sticking agent.

[0040] According to an embodiment of the present invention, the propranolol hydrochloride sustained-release tablet provided above may further include the following technical features:

[0041] According to an embodiment of the present invention, in the propranolol hydrochloride sustained-release tablet, the sustained-release film coating premix, by weight, comprises:

[0042] 20 - 25 parts by weight of ethylcellulose;

[0043] 40 - 45 parts by weight of acrylic resin;

[0044] 8 - 10 parts by weight of hydroxypropyl methylcellulose;

[0045] 12 - 18 parts by weight of plasticizer;

[0046] 8 - 10 parts by weight of lactose,

[0047] 5 - 10 parts by weight of anti-sticking agent.

[0048] According to an embodiment of the present invention, in the propranolol hydrochloride sustained-release tablet, the sustained-release film coating premix, by weight, comprises:

[0049] 25 parts by weight of ethylcellulose;

[0050] 40 parts by weight of an acrylic resin;

[0051] 10 parts by weight of hydroxypropyl methylcellulose;

[0052] 15 parts by weight of a plasticizer;

[0053] 8 parts by weight of lactose,

[0054] 5 parts by weight of talc,

[0055] 5 parts by weight of silicon dioxide.

[0056] According to an embodiment of the present invention, in the propranolol hydrochloride sustained-release tablets, the anti-adhesive agent is talc or silicon dioxide.

[0057] According to an embodiment of the present invention, in the propranolol hydrochloride sustained-release tablets, the acrylic resin is Eudragit RL100.

[0058] In a third aspect of the present invention, there is provided a method for preparing the propranolol hydrochloride sustained-release tablets described in the second aspect above, comprising:

[0059] Mix ethylcellulose, acrylic resin, hydroxypropyl methylcellulose, PEG400, lactose and an anti-adhesive agent, dissolve them in ethanol with a volume concentration of 80%, and stir until completely dissolved to prepare a uniform coating solution;

[0060] Put the propranolol hydrochloride tablet cores into a coating machine, spray the coating solution for coating, and after the coating is completed, dry to obtain the propranolol hydrochloride sustained-release tablets.

[0061] According to an embodiment of the present invention, the propranolol hydrochloride tablet cores are prepared by the following method:

[0062] Pass the propranolol hydrochloride raw material, hydroxypropyl methylcellulose, and lactose through an 80-mesh sieve respectively, then mix them evenly according to a predetermined ratio, and add 75% ethanol as a wetting agent to prepare a soft material;

[0063] Pass the soft material through an 18-mesh sieve to granulate, and dry the obtained wet granules at 50 °C until the moisture content is 2.5% - 5% to obtain dry granules;

[0064] Pass the dry granules through an 18-mesh sieve for sizing, add 1% magnesium stearate and mix evenly, and press tablets to obtain the propranolol hydrochloride tablet cores. Detailed Description of the Embodiments

[0065] The embodiments of the present invention will be described in detail below. The embodiments are exemplary and are intended to explain the present invention and should not be construed as a limitation to the present invention.

[0066] The present invention provides a propranolol hydrochloride sustained-release tablet, comprising: 92 to 94 parts by weight of a propranolol hydrochloride tablet core and 6 to 8 parts by weight of a sustained-release film coating premix, and the sustained-release film coating premix forms a coating on the surface of the propranolol hydrochloride tablet core;

[0067] The sustained-release film coating premix, by weight, comprises:

[0068] 20 - 25 parts by weight of ethylcellulose;

[0069] 40 - 50 parts by weight of acrylic resin;

[0070] 5 - 15 parts by weight of hydroxypropyl methylcellulose;

[0071] 10 - 20 parts by weight of PEG400;

[0072] 8 to 12 parts by weight of lactose,

[0073] 5 - 10 parts by weight of an anti-adhesive agent.

[0074] According to a specific embodiment, the sustained-release film coating premix, by weight, comprises:

[0075] 20 - 25 parts by weight of ethylcellulose;

[0076] 40 - 45 parts by weight of acrylic resin;

[0077] 8 - 10 parts by weight of hydroxypropyl methylcellulose;

[0078] 12 - 18 parts by weight of a plasticizer;

[0079] 8 to 10 parts by weight of lactose,

[0080] 5 - 10 parts by weight of an anti-adhesive agent.

[0081] According to a specific embodiment, the sustained-release film coating premix, by weight, comprises:

[0082] 25 parts by weight of ethylcellulose;

[0083] 40 parts by weight of acrylic resin;

[0084] 10 parts by weight of hydroxypropyl methylcellulose;

[0085] 15 parts by weight of a plasticizer;

[0086] 8 parts by weight of lactose,

[0087] 5 parts by weight of talc,

[0088] 5 parts by weight of silicon dioxide.

[0089] The mentioned anti-adhesive agent is talc or silica.

[0090] The mentioned acrylic resin is Eudragit RL100. As an acrylic resin, Eudragit RL100 has various advantages compared with other types of acrylic resins (such as Eudragit RS series, enteric-coated L / S series, etc.). For example, Eudragit RL100 contains a relatively high proportion of quaternary ammonium salt groups (trimethylammonium ethyl methacrylate chloride). These strongly hydrophilic groups cause its film to swell through ion exclusion when contacting an aqueous medium, forming a relatively large pore structure (pore diameter 1 - 5 μm). In contrast, Eudragit RS100 has a lower content of quaternary ammonium salt groups and a smaller pore diameter (0.1 - 0.6 μm), resulting in poorer permeability. This high permeability enables RL100 to more flexibly control the drug release rate, especially suitable for formulations requiring rapid or moderate sustained release. Moreover, different from enteric-coated acrylic resins (such as Eudragit L / S series), the sustained release characteristics of RL100 are not affected by changes in gastrointestinal pH. Also, RL100 has a low viscosity and good fluidity in solvents, and the solvent volatilizes rapidly after coating (forming a film in about 20 seconds), forming a uniform and mechanically stable film. The sustained release tablets prepared therefrom have better performance.

[0091] The mentioned propranolol hydrochloride sustained release tablets can be prepared by the following method, including:

[0092] Mix ethylcellulose, acrylic resin, hydroxypropyl methylcellulose, PEG400, lactose and anti-adhesive agent, dissolve them in ethanol with a volume concentration of 80%, and stir until completely dissolved to prepare a uniform coating solution;

[0093] Put the propranolol hydrochloride tablet cores into a coating machine, spray the coating solution for coating, and after the coating is completed, dry to obtain propranolol hydrochloride sustained release tablets.

[0094] According to the examples of the present invention, the propranolol hydrochloride tablet cores are prepared by the following method:

[0095] Pass the propranolol hydrochloride raw material, hydroxypropyl methylcellulose, and lactose through an 80-mesh sieve respectively, then mix them evenly according to a predetermined ratio, and add 75% ethanol as a wetting agent to prepare a soft material;

[0096] Pass the soft material through an 18-mesh sieve for granulation, and dry the obtained wet granules at 50 °C until the moisture content is 2.5% - 5% to obtain dry granules;

[0097] Pass the dry granules through an 18-mesh sieve for sizing, add 1% magnesium stearate and mix evenly, and press tablets to obtain the propranolol hydrochloride tablet cores.

[0098] According to the specific embodiments, the mentioned predetermined ratio is that the ratio of propanolol hydrochloride API, hydroxypropyl methylcellulose, and lactose is 15:1:1.5. The technical solutions of the present invention will be described below through specific examples. It should be noted that these examples are only for the convenience of those skilled in the art to understand and should not be regarded as a limitation on the protection scope of the present invention. The reagents used in the examples can all be obtained through commercial purchase. For example, the hydroxypropyl methylcellulose used is of the 2910 type with a viscosity of 0.005 - 0.075 pa.s. The acrylic resin used is Eudragit RL100. The anti-adhesive agents used are talc powder and silicon dioxide, and the mass ratio of the two is 1:1.

[0099] Example 1

[0100] The auxiliary components of the sustained-release film coating premix provided in Example 1 are shown in Table 1 below.

[0101] Example 2

[0102] The auxiliary components of the sustained-release film coating premix provided in Example 2 are shown in Table 1 below.

[0103] Example 3

[0104] The auxiliary components of the sustained-release film coating premix provided in Example 3 are shown in Table 1 below.

[0105] Comparative Example 1

[0106] The auxiliary components of the sustained-release film coating premix provided in Comparative Example 1 are shown in Table 1 below.

[0107] Comparative Example 2

[0108] The auxiliary components of the sustained-release film coating premix provided in Comparative Example 2 are shown in Table 1 below.

[0109] Comparative Example 3

[0110] The auxiliary components of the sustained-release film coating premix provided in Comparative Example 3 are shown in Table 1 below.

[0111] Comparative Example 4

[0112] The auxiliary components of the sustained-release film coating premix provided in Comparative Example 4 are shown in Table 1 below.

[0113] Table 1 Formulations of the sustained-release film coating premix used in different examples and comparative examples

[0114]

[0115] The hydrochloric acid pronanol tablets cores of each of the examples and comparative examples were prepared by the following method:

[0116] 1) Sieved the main drug of hydrochloric acid pronanol, hydroxypropyl methylcellulose (HPMC), lactose and other excipients through a 80-mesh sieve respectively to ensure the uniformity of the powder fineness;

[0117] 2) Weighed the main drug of hydrochloric acid pronanol, HPMC, lactose (15:1:1.5) according to the proportion, mixed them evenly, and added an appropriate amount of ethanol (ethanol with a concentration of 75%) as a wetting agent to make soft materials;

[0118] 3) Granulated through a 18-mesh sieve, and dried the wet granules at 50°C until the moisture content was 2.5%-5%.

[0119] 4) Screened the dry granules through a 18-mesh sieve for sizing, added 1% magnesium stearate by weight, and mixed them evenly;

[0120] 5) Compressed into tablet cores, with a tablet weight of about 200±5mg, a hardness of 5-6kg, and a tablet diameter of 8.5mm.

[0121] Then put the tablet cores into a coating machine, sprayed the coating solution, and controlled the coating weight gain to about 7% of the tablet core weight. After the coating was completed, dried for another 10-15 minutes to ensure the curing of the coating film. Among them, a high-efficiency coating machine was used, with the rolling speed set at 32r / min, the inlet air temperature at 75°C, the exhaust air temperature at 30-33°C, and the tablet bed temperature at 34-37°C. The spray gun pressure was 2.5kg / cm 2 , the distance of the spray gun was 13-15cm, and the spraying speed was 7mL / min.

[0122] The following studies were carried out on the hydrochloric acid propranolol sustained-release tablets prepared in the above examples and comparative examples, and the immediate-release tablets were used as a control (the immediate-release tablets mentioned here are the hydrochloric acid propranolol tablet cores):

[0123] First, in order to verify the sustained-release effect of the prepared hydrochloric acid propranolol sustained-release tablets, the following experiments were carried out:

[0124] (1) In vitro dissolution test: Used the USP method II (paddle method) to carry out the dissolution test in hydrochloric acid solution with pH 1.2, and recorded the dissolution amounts at different time points.

[0125] It was found that the dissolution curves of the propranolol hydrochloride sustained-release tablets prepared in Examples 1-3 should be significantly different from those of the immediate-release tablets, usually manifested as a slower dissolution rate of the sustained-release tablets and a smaller fluctuation in peak and trough concentrations. Specifically, in the hydrochloric acid solution with pH 1.2, the dissolution amount of the sustained-release tablets is less within the first 30 minutes, then gradually increases, reaches the peak at 6 hours, and then tends to be stable. Generally speaking, the sustained-release tablets show a stable release curve within 24 hours, and the release amount at 12 hours is about 60% - 80%. Compared with the immediate-release tablets, the dissolution curve of the sustained-release tablets is flatter and the fluctuation of peak and trough concentrations is smaller.

[0126] Moreover, compared with Comparative Examples 1-4, although the dissolution rate of Comparative Examples 1-4 is also slower compared to the immediate-release tablets, the change is not obvious. The effects of Comparative Examples 1-4 are significantly inferior to those of Examples 1-3.

[0127] (2) In vitro release test: Using USP Method IV (basket method), the release test was carried out in phosphate buffer solution with pH 6.8, and the release amounts at different time points were recorded.

[0128] It was found in the experimental results that in the phosphate buffer solution with pH 6.8, the release rate of the sustained-release tablets was relatively stable, the release amount was less within the first 2 hours, then gradually increased, reached the peak at 12 hours, and then tended to be stable.

[0129] Results: The release curves of the propranolol hydrochloride sustained-release tablets prepared in Examples 1-3 all showed the characteristics of continuous release and relatively stable release rate. Moreover, the sustained-release effects of Comparative Examples 1-4 were much worse than those of Examples 1-3.

[0130] Comparing the above results, among Examples 1-3, especially the effect of Example 3 was more excellent.

[0131] (3) Bioavailability test: Through a double crossover test, the plasma concentration-time curve (PK analysis) of the propranolol hydrochloride sustained-release tablets prepared in Example 3 and the immediate-release tablets in healthy volunteers was compared.

[0132] It was found that the AUC (area under the curve) of the propranolol hydrochloride sustained-release tablets prepared in Example 3 was comparable to that of the immediate-release tablets, but the peak concentration (Cmax) and time to peak concentration (Tmax) were both prolonged.

[0133] Specifically, after healthy volunteers took the sustained-release tablets, the plasma concentration-time curve showed that the AUC was comparable to that of the immediate-release tablets, but the Cmax and Tmax were prolonged by about 30% and 50% respectively. The experimental results showed that the sustained-release tablets had a good sustained-release effect.

[0134] Through the above experimental verification, it can be confirmed that the prepared propranolol hydrochloride sustained-release tablets have good sustained-release performance, can effectively prolong the action time of the drug in the body, reduce the number of drug administrations, and improve the compliance and treatment effect of patients.

[0135] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. Use of a sustained-release film coating premix in the preparation of propranolol hydrochloride sustained-release tablets, characterized in that: The sustained-release film coating premix comprises, by weight: 20-25 parts by weight of ethyl cellulose; 40-50 parts by weight of acrylic resin; 5-15 parts by weight of hydroxypropyl methylcellulose; 10-20 parts by weight of PEG400; 8 to 12 parts by weight of lactose; 5-10 parts by weight of anti-sticking agent.

2. The use according to claim 1, characterized in that The sustained-release film coating premix comprises, by weight: 20-25 parts by weight of ethyl cellulose; 40-45 parts by weight of acrylic resin; 8-10 parts by weight of hydroxypropyl methylcellulose; 12-18 parts by weight of PEG400; 8 to 10 parts by weight of lactose, 5-10 parts by weight of anti-sticking agent.

3. The use according to claim 1, characterized in that The anti-sticking agent is talc or silicon dioxide.

4. The use according to claim 1, characterized in that The acrylic resin is Eudragit RL100.

5. A propranolol hydrochloride sustained-release tablet, characterized in that: include: 92-94 parts by weight of propranolol hydrochloride core tablets and 6-8 parts by weight of a sustained-release film coating premix, wherein the sustained-release film coating premix forms a coating on the surface of the propranolol hydrochloride core tablets; The sustained-release film coating premix comprises, by weight: 20-25 parts by weight of ethyl cellulose; 40-50 parts by weight of acrylic resin; 5-15 parts by weight of hydroxypropyl methylcellulose; 10-20 parts by weight of PEG400; 8 to 12 parts by weight of lactose; 5-10 parts by weight of anti-sticking agent.

6. The propranolol hydrochloride sustained-release tablet according to claim 5, characterized in that: The sustained-release film coating premix comprises, by weight: 20-25 parts by weight of ethyl cellulose; 40-45 parts by weight of acrylic resin; 8-10 parts by weight of hydroxypropyl methylcellulose; 12-18 parts by weight of PEG400; 8 to 10 parts by weight of lactose, 5-10 parts by weight of anti-sticking agent.

7. The propranolol hydrochloride sustained-release tablet according to claim 5, characterized in that: The anti-sticking agent is talc or silicon dioxide.

8. The propranolol hydrochloride sustained-release tablet according to claim 5, characterized in that: The acrylic resin is Eudragit RL100.

9. The method for preparing the propranolol hydrochloride sustained-release tablets according to any one of claims 5 to 8, characterized in that: include: Ethyl cellulose, acrylic resin, hydroxypropyl methyl cellulose, PEG400, lactose and an anti-adherent are mixed, dissolved in ethanol with a volume concentration of 80%, and stirred until completely dissolved to prepare a uniform coating solution; The core of the pronol hydrochloride tablet is put into a coating machine, and the coating liquid is sprayed therein for coating. After the coating is completed, the tablet is dried to obtain the pronol hydrochloride sustained-release tablet.

10. The method for preparing the propranolol hydrochloride sustained-release tablets according to claim 9, characterized in that: The Propranolol Hydrochloride Tablet Core is prepared by the following method: The propranolol hydrochloride raw material, hydroxypropyl methylcellulose and lactose are respectively passed through an 80-mesh sieve, then mixed evenly according to a predetermined ratio, and 75% ethanol is added as a wetting agent to prepare a soft material; The soft material is granulated through an 18-mesh sieve, and the obtained wet granules are dried at 50 degrees Celsius to a moisture content of 2.5% to 5% to obtain dry granules; The dry granules are sieved through an 18-mesh sieve, 1% magnesium stearate is added and mixed evenly, and tableting is performed to obtain the propanol hydrochloride tablet core.

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