Ambroxol hydrochloride; Sustained-release pellets; Release degree
China Library ClassificationNo.: R944.4 Document ID: A DocumentNo.:1006-1533 (2012)15-0051-02.
Ambroxol hydrochloride is mainly used for various acute and chronic respiratory diseases accompanied by expectoration and excessive mucus secretion. It was listed in Germany in the early 1980s, and then in Japan, Spain, Italy, France and other countries. Ambroxol hydrochloride has been used in clinic since 199 1 year in China, and its clinical efficacy and safety have been confirmed. Ambroxol hydrochloride is the active metabolite of bromhexine, which can promote the emptying of bronchial cilia and the discharge of airway secretions, with low toxicity and strong expectorant and pulmonary function improvement. A variety of dosage forms have been listed abroad, which is one of the most commonly used expectorant drugs. In this paper, ambroxol hydrochloride sustained-release pellets were prepared, which only need to be taken/kloc-0 times a day, and the preparation quickly disintegrated into tiny sustained-release drug units in gastrointestinal tract. As a multi-unit delivery system, it has the advantages of uniform distribution in the gastrointestinal tract, reducing gastrointestinal irritation or adverse reactions caused by local drug concentration [1], little influence of food delivery rhythm on gastrointestinal transport, and small individual differences [2]. The preparation can be swallowed or washed with water, which is especially convenient for children, the elderly and other special people with dysphagia, and increases the compliance of treatment.
1 instrument and reagent testing
ZRS-8G Intelligent Dissolution Instrument (Tianjin University Wireless Power Plant); Tablet hardness tester (Shanghai Huanghai Drug Inspection Instrument Factory); UV-2450 ultraviolet-visible spectrophotometer (Shimadzu Company, Japan); Grate GPCG- 1. 1 fluidized bed (Grate, Germany); Single punch tablet press (National Medicine Longli Pharmaceutical Machinery Company).
Ambroxol hydrochloride (produced by Shaanxi Hanjiang Pharmaceutical Group Co., Ltd., batch number: 0510007); Utec NE30D (Degussa China investment co., ltd., batch number: B0508 12058).
2 preparation method
2. Preparation of1ambroxol hydrochloride granules
Mix the main drug and microcrystalline cellulose evenly, add a proper amount of 6% (w: w) polyvinylpyrrolidone (K90) aqueous solution as a binder, fully stir and moisten to make a soft material, granulate with a 40-mesh sieve, dry at 45℃ for 2 h, and granulate with a 30-mesh sieve to obtain the drug-containing granules.
2.2 Preparation of Ambroxol Hydrochloride Sustained Release Coated Pellets
Add talcum powder into proper amount of water, homogenize with a homogenizer for 5 min, mix the solutions, stir them evenly, and slowly add them into the water dispersion of NE30D in Utrecht with stirring. The drug-containing particles were coated with polymer by bottom spraying technology. The temperature of coating material is 25℃, the atomization pressure is 65438±0.5 bar, and the weight gain of coated polymer is about 8%. After coating, the coated pellets were spread on a flat plate, dried in an oven at 40℃ for 6 h, and granulated to obtain coated pellets.
2.3 Preparation of Sustained Release Pellet Tablets
According to the principle of equal increase, the coated granules were evenly mixed with a certain amount of microcrystalline cellulose, sodium carboxymethyl starch and other auxiliary materials, and tabletted to obtain ambroxol hydrochloride sustained-release pellets containing 75 mg of ambroxol hydrochloride per granule.
Three results
3. 1 release assay
According to the dissolution determination method (China Pharmacopoeia Appendix XD Ⅱ method, version 20 10), the dissolution determination method (China Pharmacopoeia Appendix XC Ⅱ method, version 20 10) was used, and sodium chloride-hydrochloric acid solution 1 000 ml was used as the release medium, with 50 rpm and/kloc- Immediately take phosphate buffer solution with pH of 6.8 (100ml for 2 h and 4 h), and then sample it, and measure the absorbance at 244 nm according to ultraviolet-visible spectrophotometry (Appendix IV A of China Pharmacopoeia 20 10). In addition, an appropriate amount of ambroxol hydrochloride reference substance was accurately weighed to make a solution containing about 25 μg per kloc-0/ml, and the solution was determined by the same method. The release amount of each tablet at different time was calculated respectively. See table 1 for the determination results of sustained-release pellets and cumulative release of pellets.
The results showed that the cumulative release rate of sustained-release coated pellets had no obvious change at each time point before and after tabletting, which indicated that the release behavior of pellets before and after tabletting was basically the same.
3.2 Study on Weight Increase of Coating Polymer
It was found that the release rate of the prepared sustained-release pellets was related to the weight gain of the polymer. The release of drug-containing particles with different weight gain was measured. The release curve is shown in figure 1, and the polymer weight increases by 5%, 8%, 15% and 20% respectively.
The results show that with the increase of coating weight, the film thickness increases and the release rate slows down obviously. By controlling the appropriate coating weight gain, the release rate can be effectively adjusted to meet the predetermined requirements.
3.3 Investigation of tabletting force and hardness
Under the same prescription, sustained-release dispersible tablets with different hardness were pressed under different pressures, and their release, disintegration time and brittleness were investigated respectively. The results are shown in Table 2.
The results show that the hardness of the pellets is too small, the brittleness is obviously increased, the hardness is too large (more than 12 kg), and the release rate does not meet the requirements (late sustained release). When the hardness is controlled at 5 ~ 8 kg, the release rate and brittleness meet the design requirements.
4 discussion
The preparation process of ambroxol hydrochloride sustained-release pellets is simple and easy to industrialize. Neutral methacrylic acid * * * polymer (NE30D) is selected as the coating material of granular film, and a water-insoluble soft film can be formed on the surface of granular film. The film can swell in water and has permeability. Because the polymer film has strong flexibility, it will not break when it is deformed, and it can bear the impact of the mold when it is pressed. When the hardness is too high (more than 12 kg), the tablet is not completely released in the later stage, which may be due to its strength. When the hardness of tablets is controlled at 5 ~ 8 kg, the release rate and brittleness meet the requirements. In the preparation process, the release rate of the preparation can be effectively adjusted by adjusting the weight gain of the polymer coating, so as to control the quality of the prepared sustained-release pellets.
refer to
[1] Beckert TE, Lehmann K, Schmidt PC, et a 1 pressing enteric-coated pellets into disintegrating tablets [J]. international pharmaceutical, 1996,143 (11).
[2] Debner A, Virva Ette C, Manglins D, et a 1. Compression of enteric-coated pellets: effects of prescription and process parameters on tablet properties and in vivo evaluation [J]. European Journal of Pharmaceutical Science. 2004, 22(4): 305-3 14.
(Date of receipt: 20 12-04-0 1)