Preclinical Studies Of Ibuprofen And Diphenhydramine HCl Orally Disintegrating Tablets

Ibuprofen (IBU), an important non-steroidal anti-inflammatory drug, possesses good analgetic, anti-inflammatory and antipyretic effects. Diphenhydramine HCl (DPH), an antihistamine, also has central nervous system (CNS) depression and sedative properties. Some studies have reported that the compound can be used for the relief of occasional sleeplessness associated with minor aches and pains.It is also helpful to fall asleep and stay asleep.Currently, there are two compound preparations consisting of IBU and DPH in USA. One is the Advil(?) PM Caplets, and the other one is Advil(?) PM Liqui-Gels(?). However, it has never seen the report about the compound of ODTs, just seen the patent applied by our laboratory. IBU and DPH Orally Disintegrating Tablets (ODTs) in this article belong to the third class in our country’s new drugs registration. according to the "chemical registration requirements of the classification and reporting information" of "Drug Registration" of State Food and Drug Administration’s document of No.28,2007, author made a study on the part of its preclinical, which was for the destination of accumulation of data of IBU and DPH ODTs and clinical trials and registration.Formulation and Technology. The formulation was optimized with disintegration time and taste as reference parameters by single-factor and orthogonal experiments, The best prescription contains:Ibuprofen 200 mg, Diphenhydramine HCL 25 mg, citric acid 30 mg, MCC 115 mg, Mannitol 48.5 mg, PVPP 40 mg, Sodium lauryl sulpHate 10 mg, Magnesium Stearate 3.5 mg, Gum Arabic 1.5 mg, Aspartame 15 mg, Steviosin 1.5 mg, NaHCO3 10 mg. The orally disintegrating tablets were prepared by the techniques of wet granulation, which was simple, low cost, and ODTs were integrity and smooth with desirable taste in the mouth. The disintegration time was less than 60s, hardness was 2.5-3.5kg and tablet weight variation was in the limits range.Quality Standards. RP-HPLC methods were established for the simultaneous determination of IBU and DPH in ODTs and its dissolution in this work. The separation was performed on a Shim-pack VP-ODS C18 (150 mm×4.6 mm,5μm) column. The mobile phases of determination and dissolution were a mixture of 0.05 mol/l potassium dihydrogen phosphate buffer (containing 0.2% triethylamine and 0.2% glacial acetic acid)-acetonitrile (54:46, v/v) and a mixture of 0.05 mol/1 potassium dihydrogen phosphate buffer-acetonitrile-triethylamine (60:40:0.2) respectively. The mobile phase was delivered at a flow rate of 1.0 ml/min, and the detection was carried out at 263 nm under the column temperature of 30℃and the injection volume of 20μL. Under these conditions IBU and DPH were well separated from additives and solvent, the numbers of theoretical plates were not less than 3000, and resolutions were greater than 1.5. The methods were simple, sensitive, accurate and specific. At the same time, we made a preliminary study on character, identification and inspection of IBU and DPH ODTs. Identification was sensitive, disintegration time, dissolution and content were all accord with the ODTs’ requirements. At last the protocol of IBU and DPH ODTs’ quality standards was established.Stability. The stress testing, accelerated testing and long-term testing were conducted to investigate the changes of IBU and DPH ODTs. The condition of light testing was keeping the strong light(4500±500 Lx) for 10 days; The condition of accelerated testing was RH75%±5% and the temperature was 40℃±2℃for 6 months; The condition of long-term testing was RH60%±10% and the temperature was 25℃±2℃for 9 months. Stability test showed that IBU and DPH ODTs should be stored from light and avoid excessive heat, the character of crude drug and adjuvant were stable.General pharmacology. A low, medium and high dose of IBU and DPH ODTs were designed by the method of corrected for body surface area between the people and animals. And the relationship of the three dosages between locomotor activity, coordination function and hypnosis function of subthreshold dose of Pentobarbital of mice and blood pressure, heart rate and respiratory frequency of rats were evaluated. The results were that the low doses of IBU and DPH ODTs had no significant effects on locomotor activity and coordination (P>0.05), no significant coordination functions with subthreshold dose of Pentobarbital (P>0.05), but medium and high doses had effect on locomotor activity and coordination (P<0.05). The low, medium and high doses of IBU and DPH ODTs had no significant effect on blood pressure, heart rate and respiratory frequency (P>0.05).Pharmacokinetics and bioavailability. By the self-built RP-HPLC methods, we determined the plasma concentration level of IBU and DPH in beagles from different time after administration of IBU and DPH ODTs, Advil(?) PM Liqui-Gels(?) and conventional tablets. We investigated the pharmacokinetic characteristic of IBU and DPH ODTs in beagles and compared the relative bioavailability of ODTs, Liqui-Gels and conventional tablets. The results were the Tmax and Cmax of IBU were 1.375 h,191.72 mg·L-1 and the Tmax and Cmax of DPH were 3 h,69.677 mg·L-1 of ODTs; Tmax was 2 h, Cmax was 175.038 mg·L-1 of IBU and Tmax was 3.75 h, Cmax was 68.898 mg·L-1 of common tablets; the Tmax and Cmax of IBU were 1.75 h,191.72 mg·L-1 and the Tmax and Cmax of DPH were 3.25,179.507 mg·L-1 of Advil(?) PM Liqui-Gels(?). The Tmax and Cmax of IBU and DPH ODTs were significantly earlier than conventional tablets (P<0.05), but not significantly earlier than Advil(?) PM Liqui-Gels(?). The results showed that IBU and DPH ODTs reached the design requirements.