| Objective:Compound Vitamines for Injection(3) was composed of Vitamin C, Vitamin B1 and Riboflavin Sodium Phosphate,which was developed by Fuso Pharmaceutical Industries, Ltd., Japan. It was firstly listed in 1985. Compound Vitamin (3) Injection mainly for the supply of vitamins,which required a lot of vitamin supplements while not fully absorbed through food use, such as consumptive disease,pregnant women,breast feeding women. With the change of the concept of clinical medicine and improvement of people’s living standards,patients with indications for the use of parenteral nutrition have been accepted by the increasing number of medical workers, subsequently, the concept of parenteral nutrition are spreading to users at large.Compound Vitamines for Injection(3) was researched and developed, which was able to compensate for the gaps in the product of domestic, and increased patient medication’s selection.Compound Vitamines for Injection(3) belonged to compound preparation, it is consisted of Vitamin C 200mg,Vitamin B1 10mg,Riboflavin Sodium Phosphate 5mg.This product was marketed in Japan as a small volume injection dosage,specifications for 5ml per ampule.The related substances from multicomponents were increased significantly,if formulation a small volume injections were sterilized by moist heat sterilization,therefore, formulation of multicomponent was concluded that fractional component of formulation were sensitive to temperature,so product safety could not be guaranteed to better level,if reduced sterilization conditions could not be met Fo value of 8,the method of sterilization affected by the level of product’s sterile. In this study, sterile lyophilized preparation was freeze-dried after drug prepared by sterilizing filtration,which could effectively avoid degradation of drug caused by high temperature sterilization, therefore products and produced related substances were decreased partly. Injection of sterile lyophilized formulations possessed good quality, such as transportation more convenient, and obviously feasible process, which were more conducive to industrial products.Methods:Considering the physical and chemical properties of different formulations, such as Vitamin C, Vitamin B1, Riboflavin Sodium Phosphate,and reference compound Vitamin (3) Injection,three primary drugs single preparations, compound water-soluble vitamins and other related information,series of item, such as appearance of formulations, reproducibility of solubility, pH,content of each of the main drug,and related substances,could be investigated completely.In order to understand the composition of prescription, the type and amount of excipients,metal ion complexing agent, acidity regulators and freeze-drying process were extensively studied in follow experiments. Finally, ultima of the formulation and preparation process were determined by experimental results.Through systematic study of quality, ultimately simultaneous determination of compound preparation of three active ingredients, related substances of vitamin C,vitamin B1,riboflavin sodium phosphate and oxalic acid were determined by means of using different chromatographic conditions by HPLC. The chromatographic conditions were optimized, and ultimately determined the concent of three ingredients, and three batches of samples were tested for the stability study by developed standards.Results:Finally, in compound preparation, glycine as excipient,the amount was 100mg per bottle,EDTA as metal ion complexing agent,sodium bicarbonate as acidity regulator,the amount of activated carbon was 0.01%,communion point was -32℃.The finalized production process was carried out as follow,firstly the filtered liquid was tested by means of detecting characters of intermediates, pH and content. Each bottle was filled filtered liquid with partially stoppered, placed subsequently in lyophilized box, and adopted follow procedures,freezed drying of liquid,tamponaded into the gas and out of the box,laterly taken in rolling mouth plastic combination cover, labeled signal after passing visual inspection, finally be packaged and stored.The quality results showed that content and related substances methods for Vitamin C,Vitamin B1,Riboflavin Sodium Phosphate as well as oxalic check,were simple,convenient,accurate,specificity and sensitivity, which could be used to detect Compound Vitamines for Injection(3), and eventually established the quality standards of Compound Vitamines for Injection(3).The results of factors test showed that high light and temperature had significant effect on the stability of product. Therefore these products should be saved in airtight bottles and stored at cool dark place.The compatibility test results showed that these products belonged to security in compatibility use with 5% glucose injection,10% glucose injection, 0.9% sodium chloride injection,glucose and sodium chloride injection and compound amino acid injection in clinical use.The stability test results showed that these product were stable under the conditions 30℃, RH75% within six months and 25℃, RH60% within twelve months,which indicated with no significant difference between the original data.Conclusion:Study on selection and preparation process of the preparation of compound prescription research, optimal product prescription and large-scale production process parameters were completely understanded and three batches of test samples were tested in workshop. The results showed that using proposed prescription and process parameters would be able to produce qualified products.Through chromatographic conditions select, optimization, methodology research of the components related substances inspection and determination of compound preparation, finally these products were determined quality standards, and three batches pilot-scale sample were tested with optimal quality standard. The results showed that the quality of three batches pilot-scale sample met the standards, test methods were accurate and reliable and standards of quality were reasonable.As could be studyed from stability data, the product was stable under acceleration testing conditions in six months and long-term testing conditions in twelve months, various excipients and the main drug had better compatibility, product quality was stable, which could met the requirements of clinical trial. According to the results of affecting factors, the product should be stored in dark and cool conditions. According to the accelerated and long-term results, the product was valid for 24 months provisionally.Summary, the compound preparation was rational designed, for instance process route was viable, reproducibility was better, established analysis was feasibile, quality standards was reasonable. In pilot-scale sample pass quality inspection, impurity was controllable, which could be used in clinical studies. |
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