Benzonatate sustained release tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a benzonatate sustained release tablet and a preparation method thereof. According to the invention, the mixture of calcium phosphate and calcium silicate is adopted to adsorb benzonatate, and then the filler, the sustained-release material, the coating agent, the adhesive, the lubricant and the like are added to prepare the sustained-release tablet, so that the administration frequency can be reduced, the paralysis risk can be reduced, the drug release speed within 12 hours is moderate, the administration compliance of patients is improved, and the sustained-release tablet is simple in preparation method and low in cost. Good application prospects are realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sustained-release benzonatate tablet and a preparation method thereof. BACKGROUND

[0002] Benzonatate is a peripheral antitussive drug. Peripheral antitussive drugs are combined with receptors on the afferent nerves, efferent nerves, and effectors in the cough reflex arc to produce an antitussive effect. Benzonatate is currently available in 100 mg and 200 mg capsules, with a maximum daily dosage of 600 mg per day, and is not approved for use in children under the age of 10. In 2010, benzonatate received a black box warning due to the fact that the capsules resemble candy, and there is a risk of numbing the mouth and throat when the capsules are broken by sucking or chewing. At the same time, the fact that benzonatate capsules are administered three times a day further increases the risk of numbing. At present, no other dosage form other than the capsule has been developed at home and abroad, and therefore, there is an urgent need to develop a sustained-release tablet that can reduce the frequency of administration and the risk of numbing the mouth and throat. SUMMARY

[0003] The purpose of the present application is to provide a sustained-release benzonatate tablet that can reduce the frequency of administration and the risk of numbing the mouth and throat.

[0004] Another purpose of the present application is to provide a method for preparing a sustained-release tablet with the above-mentioned excellent properties by traditional equipment without special equipment, which is excellent in terms of industrial production.

[0005] The technical solution of the present application is as follows:

[0006] A sustained-release benzonatate tablet comprising benzonatate and an adsorbent, wherein the adsorbent is calcium phosphate and calcium silicate.

[0007] In some embodiments, the weight ratio of calcium phosphate to calcium silicate is 3:1 to 1:2.

[0008] In some embodiments, the weight ratio of benzonatate to the adsorbent is 2:1 to 1:3.

[0009] In some embodiments, the sustained-release tablet further comprises a filler, a sustained-release material, a coating agent, a binder, and a lubricant.

[0010] In some embodiments, the filler comprises one or more of anhydrous dibasic calcium phosphate, lactose, microcrystalline cellulose; the sustained-release material comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate; the coating agent comprises methacrylic acid ester copolymer, methacrylic acid and ethyl acrylate copolymer, methacrylic acid methyl ester and diethylaminoethyl methacrylate copolymer; the binder comprises one or more of povidone, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, pregelatinized starch; the lubricant comprises one or more of magnesium stearate, sodium stearyl fumarate, micronized silica, talc, hydrogenated vegetable oil, polyethylene glycol.

[0011] In some embodiments, the sustained-release tablet comprises, by weight fraction, 15-20 parts of benzosonaate, 10-15 parts of calcium phosphate, 20-25 parts of calcium silicate, 20-50 parts of filler, 5-10 parts of sustained-release material, 1-5 parts of binder, 1-5 parts of lubricant and 2-5 parts of coating agent.

[0012] In some embodiments, the sustained-release tablet comprises, by weight fraction, the following components,

[0013]

[0014] The coating agent is methacrylic acid ester copolymer, and the coating weight is 3-5%.

[0015] The present application also provides a preparation method of the sustained-release tablet, comprising the following steps:

[0016] 1) Place calcium phosphate and calcium silicate in a wet granulator, set the stirring speed to 10 HZ and the cutting speed to 10 HZ, slowly add benzosonaate, and mix for 20 min; sieve the mixture through a 40-mesh sieve after mixing is completed to obtain a benzosonaate component;

[0017] 2) Dissolve the prescribed amount of binder in an appropriate amount of purified water;

[0018] 3) Granulation: add the benzosonaate component, filler and sustained-release material to a fluidized bed, spray the binder solution in a top-spray manner to perform granulation. Set the inlet air temperature to 55±5℃, the material temperature to 40℃±5℃, the fan frequency to 15±5 HZ, the atomization pressure to 2 bar, and the liquid spraying speed to 15 rpm (10-20 rpm). After the liquid spraying is completed, the material continues to be dried in the fluidized bed;

[0019] 4) Size reduction: sieve the dry granules through a 40-mesh sieve;

[0020] 5) Total mixing: mix the dry granules with the lubricant at 25 HZ for 3 min;

[0021] 6) Tablet compression: the theoretical tablet weight is 900 mg, and the hardness is controlled to be 50-80 N;

[0022] 7) Preparation of coating solution: solvent is 60% (w / w) ethanol aqueous solution, 10% (v / v) methacrylic acid amine alkyl ester copolymer is prepared into ethanol aqueous solution, and is passed through an 80-mesh sieve;

[0023] 8) Coating: upper limit of material temperature is 40.0℃, inlet air temperature is 50.0℃, upper limit of outlet air temperature is 40.0℃, lower limit of outlet air temperature is 35.0℃, main machine rotating speed is 10 rpm, inlet air rotating speed is 1900 rpm, exhaust air rotating speed is 1700 rpm, peristaltic pump rotating speed is 6 rpm, atomization pressure is 0.14 mPa, top needle pressure is 0.3 mPa, blowing pressure is 0.18 mPa, and drying is performed after coating is completed. Coating weight gain is 4%.

[0024] Advantages of the present application: firstly, the present application converts benzonast into solid through adsorbent, and then the benzonast is compressed into tablets and coated with coating material such as methacrylic acid amine alkyl ester copolymer. The polymer coating layer cannot be melted in liquid with pH 5.8 or above (pH of saliva is 6.6-7.1), that is, the sustained-release tablets enter the oral cavity, and the coating layer blocks the release of benzonast, thereby solving the risk of paralysis of the oral cavity and throat that may occur to the capsule.

[0025] Benzonast capsule is a quick-release preparation, and the antitussive time is short. The present application uses sustained-release material (such as hydroxypropyl cellulose) to prepare the sustained-release tablets. By comparing the in-vitro release curves of benzonast sustained-release tablets (test group) and benzonast soft capsules (reference group) with the in-vivo pharmacokinetic curves (average blood drug concentration-time curves) of beagles, it can be seen that the benzonast sustained-release tablets have obvious sustained-release effect and achieve the effect of sustained antitussive. Due to the sustained-release effect, the frequency of taking the medicine can be reduced, and the patient compliance can be improved. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 In-vitro release curves of reference group (benzonast capsule) and test group (benzonast sustained-release tablets)

[0027] Figure 2 In-vivo average blood drug concentration-time curves of reference group (benzonast capsule) and test group (benzonast sustained-release tablets) of beagles DETAILED DESCRIPTION

[0028] The following examples can make the skilled person in the art more fully understand the present application, but the present application is not limited in the scope of the examples.

[0029] 1. Investigation of calcium phosphate, calcium silicate and silicon dioxide as adsorbents

[0030] The same amount of calcium phosphate, calcium silicate, silicon dioxide and calcium phosphate and calcium silicate are used as adsorbents, and the adsorption capacity of benzonast is investigated.

[0031]

[0032] The preparation method of Comparative Examples 1-3 and Example 1 prescription is as follows:

[0033] The calcium phosphate / silicon calcium / silicon dioxide / calcium phosphate and silicon calcium were respectively placed in a wet granulator, the stirring speed was set to 10 HZ, the cutting was set to 10 HZ, and the benzene sonar ester was slowly added and mixed for 20 min.

[0034] Results: When single calcium phosphate / silicon calcium / silicon dioxide was used as the adsorbent, the mixed powder had obvious oily droplets, and the powder was in a humid state.

[0035] 2. Ion exchange resin (AMBERLITE IRP88) as adsorbent

[0036] The same amount of ion exchange resin and calcium phosphate and silicon calcium were used as adsorbents to investigate their adsorption capacity for benzene sonar ester.

[0037]

[0038] The preparation method of Example 2 is the same as that of Example 1, and the preparation method of Comparative Example 4 is as follows:

[0039] The benzene sonar ester was added to a certain amount of purified water, stirred and mixed uniformly, the ion exchange resin was added to the solution while stirring, and the stirring was continued for 1 h, and the liquid was layered after standing for 0.5 h. The liquid surface of Comparative Example 4 was obviously floating with oily substances.

[0040] Results: When the same amount of adsorbent is used, more benzene sonar ester is adsorbed by calcium phosphate and silicon calcium.

[0041] 3. Calcium phosphate and silicon calcium as adsorbent

[0042] The same amount of adsorbent was used to adsorb benzene sonar ester to compare the effect of the adsorbent on the compressibility of the tablets.

[0043]

[0044] The preparation method of Comparative Example 5 and Example 3 prescription is as follows:

[0045] (1) The adsorbent (calcium phosphate and silicon calcium / silicon dioxide) was placed in a wet granulator, the stirring speed was set to 10 HZ, the cutting was set to 10 HZ, the benzene sonar ester was slowly added, and the mixture was mixed for 20 min; the mixture was sieved through a 40-mesh screen after mixing was completed to obtain a benzene sonar ester component;

[0046] (2) Povidone K30 was dissolved in an appropriate amount of 50% ethanol aqueous solution;

[0047] (3) Granulation: the benzene sonar ester component and hydroxypropyl cellulose, lactose are added into the wet granulator, the stirring speed is set to 10HZ, the cutting is set to 10HZ, and the mixing is set to 10min; then the povidone K30 solution is added, and the granulation is performed for 5min, the stirring speed is set to 10HZ, and the cutting is set to 15HZ;

[0048] (4) Granulation: the wet granules are passed through the swing granulator, and the 18 mesh screen is used;

[0049] (5) Drying: the inlet air temperature is 60℃, and the fan frequency is 20HZ;

[0050] (6) Total mixing: the dry granules are mixed with magnesium stearate, 25HZ, 3min;

[0051] (7) Tabletting: the theoretical tablet weight is 900mg.

[0052] Results: the tablet hardness of Example 3 can be controlled at 50-70N, and the hardness of Comparative Example 5 can be controlled at about 30N, and the compressibility is poor, which can be crushed by hand. Using a mixture of calcium phosphate and calcium silicate as an adsorbent can improve the hardness of the sustained-release tablets.

[0053] 4. Preparation of benzene sonar ester sustained-release tablets

[0054] The prescription composition is as follows:

[0055] Prescription composition Example 4 (%) Benzonatate 16.7 Calcium phosphate 10 Calcium silicate 23.4 Calcium phosphate, dibasic, anhydrous 20 Lactose 19.9 Hydroxypropyl cellulose 5 Polyvidone K30 4 Magnesium stearate 1 Blister piece weight 900 mg

[0056] The coating solution is selected as 10%(v / v) methacrylic acid amine alkyl ester copolymer solution, and the coating weight control is 3%-5%.

[0057] The preparation method of the prescription of Example 4 is as follows:

[0058] (1) The calcium phosphate and calcium silicate are placed in the wet granulator, the stirring speed is set to 10HZ, the cutting is set to 10HZ, the benzene sonar ester is slowly added, and the mixing is set to 20min; after the mixing is completed, the 40 mesh screen is used, and the benzene sonar ester component is obtained;

[0059] (2) The povidone K30 is dissolved in a proper amount of purified water;

[0060] (3) Granulation: the benzene sonar ester component, anhydrous calcium hydrogen phosphate, lactose, and hydroxypropyl cellulose are added into the fluidized bed, the top spraying mode is used, and the povidone K30 solution is sprayed for granulation. The inlet air temperature is set to 55±5℃, the material temperature is set to 40℃±5℃, the fan frequency is set to 15±5HZ, the atomization pressure is set to 2bar, the spraying speed is set to 15rpm(10-20rpm), after the spraying is completed, the material continues to be dried in the fluidized bed;

[0061] (4) Granulation: the dry granules are passed through the 40 mesh screen;

[0062] (5) Total mixing: dry granules mixed with magnesium stearate, 25 HZ, 3 min;

[0063] (6) Compression: theoretical tablet weight 900 mg, hardness controlled at 50-80 N;

[0064] (7) Preparation of coating solution: solvent is 60% (w / w) ethanol aqueous solution, prepared into 10% (v / v) methacrylic acid amine alkyl ester copolymer ethanol aqueous solution, passed through an 80 mesh sieve;

[0065] (8) Coating: upper limit of material temperature 40.0°C, inlet air temperature 50.0°C, upper limit of outlet air temperature 40.0°C, lower limit of outlet air temperature 35.0°C, main machine speed 10 rpm, inlet air speed 1900 rpm, exhaust air speed 1700 rpm, peristaltic pump speed 6 rpm, atomization pressure 0.14 mPa, top needle pressure 0.3 mPa, blowing pressure 0.18 mPa. After coating, dry. Coating weight gain 4%.

[0066] 5. Results

[0067] (1) Masking effect

[0068] Since benzene sonar ester has the risk of paralyzing the oral cavity and throat, using methacrylic acid amine alkyl ester copolymer for coating can well block the release of benzene sonar ester in saliva (pH of saliva is 6.6-7.1). No benzene sonar ester was detected in the coated tablets within 10 min. The release results of coated tablets and naked tablets in a medium with pH 6.8 are as follows:

[0069]

[0070] (2) In vitro release results

[0071] The reference group is 3 benzene sonar ester capsules (size 100 mg), and the test group is 2 benzene sonar ester sustained-release tablets (size 150 mg). The release conditions are paddle method 50 rpm, 0.1N HCl (500 ml) for 1 h, then add 400 ml Na3PO4 to adjust the pH to 6.8, a total of 12 h. The release curve is shown in Figure 1 , and Figure 1 The results show that benzene sonar ester sustained-release tablets can achieve sustained-release effect in vitro.

[0072]

[0073] (3) In vivo beagle dog pharmacokinetic results

[0074] With benzoesnate capsule as reference group (dose 300mg, 3 grains), example 4 benzoesnate sustained-release tablet as test group (dose 300mg, 2 tablets), collect plasma sample at different time points, use LC-MS / MS to quantitatively detect the concentration of BBA, and obtain Figure 2 Results. From Figure 2 The results show that benzoesnate sustained-release tablet can delay the release of benzoesnate.

Claims

1. A benzonatate sustained-release tablet comprising benzonatate and an adsorbent, wherein the adsorbent is calcium phosphate and calcium silicate.

2. The sustained-release tablet according to claim 1, characterized in that The weight ratio of calcium phosphate to calcium silicate is 3:1 to 1:

2.

3. The sustained-release tablet according to claim 1, characterized in that The weight ratio of benzonatate to the adsorbent is 2:1 to 1:

3.

4. The sustained-release tablet according to claim 1, characterized in that The sustained-release tablet further comprises a filler, a sustained-release material, a coating agent, a binder and a lubricant.

5. The sustained-release tablet according to claim 4, characterized in that The filler includes one or more of anhydrous calcium hydrogen phosphate, lactose, and microcrystalline cellulose; the sustained-release material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and cellulose acetate; the coating agent includes alkyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer, and methyl methacrylate and diethylaminoethyl methacrylate copolymer; the binder includes one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, and pregelatinized starch; and the lubricant includes one or more of magnesium stearate, sodium stearyl fumarate, micropowdered silica gel, talc, hydrogenated vegetable oil, and polyethylene glycol.

6. The sustained-release tablet according to claim 4, characterized in that The sustained-release tablet comprises, by weight, 15 to 20 parts of benzonatate, 10 to 15 parts of calcium phosphate, 20 to 25 parts of calcium silicate, 20 to 50 parts of filler, 5 to 10 parts of sustained-release material, 1 to 5 parts of adhesive, 1 to 5 parts of lubricant and 2 to 5 parts of coating agent.

7. A benzonatate sustained-release tablet, characterized in that: The sustained-release tablet comprises the following components in parts by weight: The coating agent is methacrylate amine alkyl copolymer, and the coating weight gain is 3% to 5%.

8. The method for preparing the sustained-release tablet according to claim 4, comprising the following steps: 1) placing calcium phosphate and calcium silicate in a wet granulator, stirring and cutting, then slowly adding benzonatate, mixing, and sieving to obtain a benzonatate component; 2) Add the prescribed amount of adhesive to an appropriate amount of purified water and dissolve; 3) Granulation: Add the benzonatate component, filler, and sustained-release material to a fluidized bed, spray the binder solution into the fluidized bed using a top spray method to granulate the granules. After the spraying is completed, the material is dried in the fluidized bed. 4) Granulation: sieve the dry granules; 5) Total mixing: mixing dry particles with lubricant; 6) Tableting: Tableting the dry granules and lubricant mixture from step 5); 7) Preparation of coating solution: The solvent is 60% (w / w) ethanol in water, and a 10% (v / v) ethanol in water coating solution is prepared; 8) Coating: coating the plain tablets obtained in step 6) and drying after coating.

9. The method for preparing the sustained-release tablet according to claim 7, comprising the following steps: 1) Calcium phosphate and calcium silicate were placed in a wet granulator, the stirring speed was set to 10 Hz, the cutting speed was set to 10 Hz, benzonatate was slowly added, and mixed for 20 minutes; after mixing, the mixture was passed through a 40-mesh sieve to obtain the benzonatate component; 2) Add the prescribed amount of adhesive to an appropriate amount of purified water and dissolve; 3) Granulation: Add the benzonatate component, filler, and sustained-release material to a fluidized bed and spray the binder solution into the fluidized bed using a top-spray method for granulation. Set the inlet air temperature to 55±5°C, the material temperature to 40±5°C, the fan frequency to 15±5 Hz, the atomization pressure to 2 bar, and the spray speed to 15 rpm (10-20 rpm). After the spraying is completed, continue drying the material in the fluidized bed. 4) Granulation: dry granules are passed through a 40-mesh sieve; 5) Total mixing: dry granules and lubricant are mixed at 25 Hz for 3 min; 6) Tableting: Theoretical tablet weight 900 mg, hardness controlled at 50-80N; 7) Preparation of coating solution: The solvent is 60% (w / w) ethanol in water, which is prepared into 10% (v / v) methacrylate aminoalkyl copolymer in ethanol in water, and passed through an 80-mesh sieve; 8) Coating: material temperature upper limit 40.0°C, air inlet temperature 50.0°C, air outlet temperature upper limit 40.0°C, lower limit 35.0°C, main engine speed 10 rpm, air inlet speed 1900 rpm, exhaust speed 1700 rpm, peristaltic pump speed 6 rpm, atomizing pressure 0.14 mPa, ejector pressure 0.3 mPa, flattening pressure 0.18 mPa, and drying after coating; coating weight gain 4%.

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