Study on the release retarder of sustained-release tablets with hydroxypropyl methylcellulose as the backbone

Abstract: Objective: To study the effects of different retarding agents on the in vitro release of ribavirin sustained-release tablets and cephalexin sustained-release tablets made of hydroxypropyl methylcellulose (HPMC) as the backbone. Method: After granulating and tableting respectively, the in vitro release rate was determined according to the regulations of the 2000 edition of "Chinese Pharmacopoeia". Results: Different retarding agents had different effects on the in vitro release of ribavirin sustained-release tablets and cephalexin sustained-release tablets. Conclusion: As a retarding agent, ethyl cellulose is suitable for cephalexin sustained-release tablets, and stearic acid is suitable for ribavirin sustained-release tablets.

Key words: hydroxypropyl methylcellulose; release retarder; sustained-release tablet; release rate

Ribavirin sustained-release tablets and cephalexin sustained-release tablets are hydrophilic gel-type sustained-release tablets, which are composed of drugs, hydroxypropylmethylcellulose (HPMC), release retarders and other excipients. It involves the invasion of water on the tablet surface, the gelation of HPMC, the penetration of water, the gradual dissolution of the drug through the gel layer, the outer rubber layer, and the dissolution of the tablet. The influencing factors include the physical and chemical properties of the drug itself (ribavirin dissolution). In water, cephalexin is insoluble in water), HPMC viscosity, dosage, moisture content of dry granules, pressure during tableting, etc. Since the addition of HPMC should not be too much, in order to delay the release of the drug, a release retarder is indispensable. A suitable release retarder should have a greater impact on the release rate of the tablet, and can reduce the effects of other factors on its release rate, which is conducive to large-scale production.

1. Instruments and reagents

Instruments: ZP-19 Tablet Press (Shanghai Pharmaceutical Machinery Factory); 6010 UV-Vis Spectrophotometer (Agilent <Shanghai> Technology Company); 101-3 Electric Oven (Shanghai Experimental Instrument Factory); Swing Granulator (Shanghai Pharmaceutical Machinery Factory); RH-3D Drug Dissolution Apparatus (Tianjin University Experimental Instrument Factory).

Test drug: ribavirin (abbreviated as RIB, batch number: 20030501, Shandong Xinhua Pharmaceutical Co., Ltd.); cephalexin (abbreviated as CEF, batch number: 2003257, Shandong Xinhua Kenfu Pharmaceutical Co., Ltd.); stearic acid; lactose; Magnesium fatty acid; Talc powder; Ethanol; (Model: RT50, batch number: 0303-35, Shandong Ruitai Pharmaceutical Excipients Co., Ltd.); HPMC; ethyl cellulose (model: RT100, batch number: 0303-36, KIMA CHEMICAL CO., LTD).

2. Methods and results

2.1 RIB Sustained Release Tablets

2.1.1 Prescription determination

RIB (200 mg/tablet) was used as raw material, HPMC (RTK15) was used as skeleton, lactose was used as excipient, 20% ethanol was used as wetting agent, magnesium stearate and talcum powder were used as lubricant, and release inhibitors were selected respectively Ethyl cellulose (2%, 4%, 6%) and stearic acid (2%, 4%, 6%, the above percentages are the ratio of release retarder to total tablet weight), and increase according to the amount of retarder The amount of lactose was reduced to keep the tablet weight stable, and the prescriptions RIB1-RIB6 were prepared; and the prescription RIB0 was prepared without adding retarder.

2.1.2 Preparation process

Mix RIB, HPMC, lactose and retarding agent according to the prescription amount, use 20% ethanol as wetting agent to make a suitable soft material, use a swinging granulator to granulate with 20 mesh, dry at 50-60°C, 18 mesh Whole granules, dry granule moisture is controlled at 3% to 4%, add magnesium stearate and talc powder, mix well, punch out tablets with a diameter of 9 mm, the weight of the tablet is 0.31 g/tablet, and the pressure is kept at 6-7 kg /cm².

2.1.3 Release check

According to the regulations in the release item of the appendix of reference [1], the rotating basket method was adopted, water was used as the solute, the sampling time was set at 1, 2, 4, 6, 8, and 12 h, and the absorbance was measured at a wavelength of 207 nm. Calculate the degree of release.

2.1.4 In vitro release results

Sustained-release tablets prepared with prescription RIB 1-6 could maintain the prototype within 12 hours; and the swelling degree of the slices was different, and there were erosion phenomena; after the tablet core was taken out for 12 hours, RIBz and RIB were still very hard, and the other 4 tablets were still very hard. This kind of film has a hard core but not many. RIB. The in vitro release rate was fast first and then slow, with poor regularity. The release of RIB2 and RIB3 was too slow, 60% after 12 hours, and the release of RIB0 was too fast, and 98% was released within 4 hours. First-order release, especially RIB5, reached 98% after 12 h, but was still formed.

2.2 CEF Sustained Release Tablets

2.2.1 Determination of prescription

Using CEF (specification 250 mg/tablet) as raw material, HPMC (RTK15) as skeleton, lactose as excipient, 20% ethanol as wetting agent, magnesium stearate and talcum powder as lubricant, select release inhibitors respectively Ethyl cellulose (2%, 4%, 6%) and stearic acid (2%, 4%, 6%, the above percentages are the ratio of release retarder to total tablet weight), and increase according to the amount of retarder The amount of lactose was reduced to maintain the weight of the tablet, and the prescriptions CEF1-CEF6 were prepared; the prescription CEF0 was prepared without adding retarder.

2.2.2 Preparation process

Mix CEF, HPMC, lactose and release retarder according to the prescription amount, use 20% ethanol as wetting agent to make a suitable soft material, use a swinging granulator to granulate with 20 mesh, dry at 50-60°C for 18 The granules are sized, the moisture content of the dry granules is controlled at 4% to 6%, and magnesium stearate and talc powder are added to mix well, and the tablets are punched with shallow concaves with a diameter of 9 mm. kg/cm2.

2.2.3 Release check

According to the provisions of the release in the appendix of literature [1], the rotating basket method was adopted, water was used as the solute, and the sampling time was set at 1, 2, 4, 6, 8, and 12 h, and the absorbance was measured at a wavelength of 254 nm. Release.

Sustained-release tablets prepared with prescription CEF 1-6 can basically maintain the prototype within 12 hours; CEF0 dissolves over 98% within 4 hours; CEF 4-6 cracks in about 3 hours and dissolves completely after 8 hours; CEF2 and CEF3 maintained a stable corrosion state, and they were all dissolved after 12 hours, showing a good retardation effect.

2.3 Comparison of sustained-release effects between RIB and CEF

The Higuchi equation uses a first-order steady-state model and formula to describe the law of drug dissolution with time. Based on this, the author makes C—t1/2 mathematical treatment for prescription RIB5 and CEF2.

Mathematical processing is carried out according to the experimental data respectively, and relevant trend diagrams are obtained.

The results showed that ethyl cellulose had a better effect on CEF sustained-release tablets as a retarding agent, and stearic acid had a better effect on RIB sustained-release tablets as a retarding agent.

3 Discussion

(1) The release of drugs from HPMC hydrogel matrix tablets has been reported. When HPMC encounters water, it first wets the surface of the tablet to form a hydrophilic gel, which dissolves the surface drug, and the water penetrates further into the interior. The gel layer continues to hydrate, the skeleton expands, and the gel layer thickens. Considering that the size of the sheet should not be too large and the amount of HPMC is small, it is difficult to prevent the drug from diffusing into the medium only by the gel layer. The role of the release retarder is to make the surface of the gel layer of the tablet "dense" and reduce the release of the drug into the water.

(2) For the release of HPMC hydrophilic gel matrix tablets, water-soluble drugs such as RIB mainly diffuse from the matrix gel layer to the dissolution medium, so stearic acid has a better effect as a release retarder. Water-insoluble drugs such as CEF are mainly released by erosion of the matrix gel layer, so ethyl cellulose has a better effect as a release retarder.