Subscribe Now Subscribe Today
Research Article
 

Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh



A. Tabassum, R.R. Saha, M.S. Rahman, M.A. Nure, R. Karim, A.H.M.R. Imon, M. Maniruzzaman, A.K.L. Kabir, A. Islam, J.F. Chaity, B.C. Adhikary, A. Sarwar, T.B. Huq and Mst. M. Begum
 
Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail
ABSTRACT

Background and Objective: Pain management has been an area of a great deal of attention for pharmacists for many years. In this study, we report a study which is designed to investigate how a combination of existing effective drugs performs for the relief of pain management. Materials and Methods: A combined solid dosage containing paracetamol (500 mg) and ibuprofen (150 mg) is developed and tested under an observational analytical study. The performance of this combined oral solid dosage named maxigesic tablet in order to reduce pain is investigated on the basis of European patent specification. This assay is carried out by employing HPLC system with UV detection at 222 nm. Results: The results show the presence of active components to the tune of 112.12% for paracetamol and 101.86% for ibuprofen. The formulated solid dosage is further subjected to separate groups of artificially pain induced mice for a comparative study and it shows more efficacy than single analgesic used in pain management. We observe that the respective potencies for paracetamol and ibuprofenare 98.57 and 102.90%. Conclusion: The characterization of both granules and tablets of newly developed formulation demonstrates significant improvement in results of analytical test that not only met the standard specification, but they also reveal that the combined dosage will improve the product quality, efficacy and patient safety in the long run. This trial also shows a significant difference in the percentage of pain inhibition between the two sets of formulations (single and combination of them).

Services
Related Articles in ASCI
Search in Google Scholar
View Citation
Report Citation

 
  How to cite this article:

A. Tabassum, R.R. Saha, M.S. Rahman, M.A. Nure, R. Karim, A.H.M.R. Imon, M. Maniruzzaman, A.K.L. Kabir, A. Islam, J.F. Chaity, B.C. Adhikary, A. Sarwar, T.B. Huq and Mst. M. Begum, 2017. Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh. Journal of Pharmacology and Toxicology, 12: 1-13.

DOI: 10.3923/jpt.2017.1.13

URL: https://scialert.net/abstract/?doi=jpt.2017.1.13
 
Received: August 17, 2016; Accepted: November 04, 2016; Published: December 15, 2016



INTRODUCTION

The relief of pain has been described as a universal human right but is not always easily achieved1. Pain is defined by the International Association for the Study of Pain (IASP) as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage2. In Bangladesh, generally the physicians are keen to prescribe locally available painkillers or analgesics like paracetamol (Acetaminophen), aceclofenac, diclofenac, naproxen, ketorolac, ibuprofen, baclofen etc., for the treatment of mild to moderately severe pain3. The use of NSAIDs brings about high risk of having a range of gastrointestinal (GI) problems4. Common gastrointestinal ADRs include5 nausea/vomiting, dyspepsia, gastric ulceration or bleeding, diarrhea etc.5,6. However, gastric (but not necessarily intestinal) adverse effects can often be reduced through suppressing acid production by concominant use of a proton pump inhibitor like omeprazole, esomeprazole etc.7,8. Use of PPI with NSAIDs may be effective but the pain management cost becomes expensive. Even though the opioid analgesics are effective, they have troublesome and potentially dangerous side-effects which may lead to regulatory and logistical difficulties. On the other hand, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have fewer regulatory restrictions, but they too have important adverse effects that appear only in the cases of higher dose or with longer courses9. Prescribing acetaminophen and ibuprofen together is common in clinical practice10-16. Paracetamol (Acetaminophen) also known as APAP, chemically named N-acetyl-p-aminophenol is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer)17,18 with the recommended dose19 of 4 g day–1. However, in many cases, it does not provide adequate pain relief on its own. On the contrary, ibuprofen [RS-2-(4-isobutyl-phenyl) propionic acid] is one of the most potent orally active antipyretic, analgesic and Non-Steroidal Anti-Inflammatory Drug (NSAID) used extensively in the treatment of acute and chronic pain, osteoarthritis, rheumatoid arthritis and related conditions20. Ibuprofen has the advantage of a well-established safety record particularly at doses below 1.5 g day–1 in adults21. The compound is characterized by a better tolerability and GI safety profile compared with other NSAIDS21,22. Besides, paracetamol (Acetaminophen) has traditionally been considered a safe and well-established treatment option in all stages of pregnancy23 and during breast feeding24,25. At least 23 cases are reported in the literature in which infants (ages not stated) were breastfed during maternal use of ibuprofen with no adverse effects reported26-28. For the treatment of moderately severe pain, particularly in the cases of dental pain and postoperative pain, NSAIDs are often used in combination with paracetamol (Acetaminophen) resulting in additive and superior pain-relief10-12,29. In a cochrane systematic review it was reported that, after surgical removal of lower wisdom teeth the novel combination drug shows encouraging results for pain relief when compared to the single drugs30. It had been reported that, a combined dosage form of acetaminophen 500 mg and ibuprofen 150 mg per tablet (Maxigesic, AFT pharmaceuticals, New Zealand) provides superior pain relief after oral surgery compared to the use of acetaminophen or ibuprofen alone and there was no pharmacokinetic interactions between acetaminophen and ibuprofen when administered together31. Recently, it is found that, the concomitant administration of ibuprofen and paracetamol in a fixed dose combination (Maxigesic, AFT Pharmaceuticals, New Zealand) does not alter the pharmacokinetic profiles of either drug in the fasted state and there was no effect of food on the absorption from the novel fixed dose combination32. However, very limited research has been done of such efficient combination of pain killer and this combination is completely unavailable in Bangladesh. The present study was undertaken to formulate and evaluate the combined efficacy of drugs for the management of pain relief.

MATERIALS AND METHODS

Study design: This study was designed and segmented into two major steps. Firstly, a combined formulation of film-coated (immediate release) tablets containing paracetamol (500 mg) and ibuprofen (150 mg) and consequently the evaluation of quality parameters of the tablet. This was done on the basis of the formulation of paracetamol (500 mg) and ibuprofen (150 mg) of United States Patent Application Publication (Pub. No.: US2011/0275718 A1) and European Patent Specification (Pub. No.: EP1781277 B1) which has been developed by Hartley Campbell Atkinson, founder and owner of AFT Pharmaceuticals Ltd. and evaluation of tablets33,34. Secondly, determination of a comparative study of analgesic activity between single dose of paracetamol (500 mg) and the newly formulated combined dose of paracetamol (500 mg) and ibuprofen (150 mg) for the relief of mild to moderately severe pain.

Materials: The API, paracetamol (Pharmatech, Bangladesh) and ibuprofen (IOL Chemicals, India) are collectedto explore the possibility of the formulation of the desired drug. The other excipients such as Avicel-101 (Mingtai Chemicals Taiwan), maize starch (Samyung Genex, Korea), croscarmellose sodium (Mingtai Chemicals, Taiwan), methyl paraben (San Fu Chemicals Ltd., Taiwan), propyl paraben (San Fu Chemicals Ltd., Taiwan), purified talc (Fuji Kajei Co., Ltd., Japan), aerosil 200 (Evonik Industries Ltd., Germany), magnesium stearate (Perter Greven, Netherland) and chemicals such as potassium dihydrogen orthophosphate, sodium hydroxide, HPLC grade acetonitrile, diluted phosphoric acid and dipotassium hydrogen phosphate are obtained from Navana Pharmaceuticals Limited, Dhaka, Bangladesh. All chemicals and reagents are of analytical grade.

Preparation of tablets: According to the study design, APIs and excipients are carefully weighed using electrical balance (Electrolab electrical balance, India) and checked for accuracy. Paracetamol, ibuprofen, Avicel PH-101 and 40% of croscarmellose sodium are mixed together. Starch paste is prepared by suspending maize starch in hot demineralized water and later allowed to cool below 50°C. The paste is added slowly to the powder materials in the mixer to prepare wet mass. Granules are obtained by sieving through a 16 mesh sieve (1.18 mm). Then granules are dried in a hot air oven at temperature 45-60°C until the moisture content becomes 2.4% measured by moisture analyzer (Shimadzu, Japan) and sieved again through 16 mesh sieve. Prior to lubrication and compression, micromeritic properties of the granules are evaluated by angle of repose, bulk density, tapped density, hausner’s ratio and compressibility index. The evaluation is done according to the methods specified in USP29-NF24. Blended granules are introduced in tablet compression machine (Pharmachine, India) having 16.5 mm sized die-punch. The compressed tablets are coated using coating material, opadry in coating machine (Hanna Instrument, India). The coated tablets are stored in air tight container at room temperature for further analytical studies.

Evaluation for quality parameters of tablets
Test for friability, hardness and weight variation: The thickness, diameter and length of 10 tablets are determined using slide calipers scale. Weight variation is done by weighing 20 tablets of each batch using electrical balance (Electrolab electrical balance, India) followed by calculation of mean and standard deviation. The friability and hardness of tablet are checked with 10 tablets using friability tester (Roche Friabilator, India) and hardness tester (Monsanto hardness tester, India). All the quality parameters are evaluated according to the methods specified in the United States Pharmacopoeia.

Disintegration test: Disintegration time of tablets is calculated by keeping 6 tablets in each tube of disintegration apparatus (Grovers disintegration tester, India) which is allowed to run at 37±2°C. The time required to break down the tablets into particles and pass through pre-set mesh in tubes is determined.

Assay test: The assay test of paracetamol (500 mg) and ibuprofen (150 mg) within the solid dosage form was determined according to a previously reported work using HPLC system35. Standard solution was prepared as, 49 mg of standard paracetamol and 14.5 mg of standard ibuprofen were weighed and taken in a 100 mL volumetric flask and about 60 mL of mobile phase was added to this. The volumetric flask was kept in sonicator for few minutes to dissolve and the volume was filled up to 100 mL with mobile phase (diluent). From this solution 5 mL was taken using pipette in another 50 mL volumetric flask. The volume was filled up to 50 mL with mobile phase. Sample solution was prepared as 10 tablets were weighed accurately (average weight 84.75 mg) and powdered. About 85.2 g of crushed powder was taken in a 100 mL volumetric flask. Sonicator was used to dissolve the powder and the volume was filled up to 100 mL with mobile phase. After filtration, from this solution 5 mL was taken using in another 50 mL volumetric flask and volume was filled up to 50 mL with mobile phase. The sample and standard solution was analyzed at wavelength 222 nm (UV detector) and a flow rate of 0.7 mL min–1 for 15 min over RP C18 column (octadecylsilane (ODS), 150×4.6 mm, 5 μm, Phenomenex Inc., Prontosil) in HPLC system (Dionex HPLC system, model-ultimate 3000, invent technology).

Dissolution studies: Dissolution medium (0.2 M potassium buffer pH 7.2) and other dissolution conditions were used according to previously reported study36. About 0.2 M potassium buffer (pH 7.2) was prepared according to USP32-NF27. One tablet was dropped into each of the six vessels of dissolution apparatus USP type II (Electrolab dissolution tester, India) containing dissolution medium at 37.1°C and was allowed to run for 60 min. Samples were collected at 5 min interval and analyzed to study dissolution profile at HPLC system at condition of wavelength 222 nm (UV detector) and a flow rate of 0.7 mL min–1 for 15 min over RP C18 column (octadecylsilane (ODS), 150×4.6 mm, 5 μm, phenomenex Inc., prontosil) in HPLC system (Dionex HPLC system, model-ultimate 3000, invent technology).

Potency test: Potency test was conducted by introducing the six newly formulated tablets in each of the vessel containing dissolution medium of dissolution tester and it was allowed to run for 1 h. The six samples were withdrawn from each vessel, filtered with filter paper and taken in test tubes. Standard solution was prepared as done in assay test. Then samples were analyzed in HPLC system under the same conditions as assay test against standard solution of paracetamol and ibuprofen35.

Stability study: In the present study, stability studies were carried out on the combined formulation of paracetamol (500 mg) and ibuprofen (150 mg) wrapped in aluminum foil to prevent the formulation from exposure to light to simulate the aluminum packaging. The study was performed to determine the change in evaluation parameters and in vitro release profile on storage carried out at accelerated storage condition at temperature 40°C/75% RH in a humidity chamber for 3 months37. Sample were withdrawn after one month interval and evaluated for change in size, shape, color, hardness, friability, in vitro drug release pattern and drug content.

Determination of analgesic activity: In order to compare the analgesic activity of the newly formulated drug (paracetamol 500 mg and ibuprofen 150 mg) with the single dose of paracetamol (500 mg) the acetic acid induced writhing test in mice was carried out in healthy male Swiss Albino mice weighing between 30 and 35 g, aged 2 months, were purchased from the Pharmacology Laboratory of Jahangirnagar University, Dhaka, Bangladesh and were individually housed in polypropylene cages in well-ventilated rooms under hygienic conditions with a metal frame lid on its top at standard environmental conditions of temperature 24±1°C. The test protocol was carried out according to the previous study38.

Animal studies: After one week acclimatization period, the animals are divided into four different groups with ten animals in each. These test animals are marked individually and food is withdrawn 12 h prior to drug administration. The standard solution (paracetamol only) and test solution (paracetamol in combination with ibuprofen) are given orally to the animals of two groups (standard and test groups) by using a feeding needle. After 60 min, pain is induced by intra-peritonial injection of 1% acetic acid (0.01 mL g–1 b.wt.) to the animals of three groups (control, standard and test groups) while one group is kept normal without inducing pain. After 5 min elapse time, writhing episodes are recorded for 10 min and the average writhes in each group is calculated. Percentage inhibition of writhing is calculated using the following equation:

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh

Statistical analysis: For statistical analysis of analgesic activity, GraphPad Prism (version 4.0) computer program (GraphPad Software San Diego, CA, USA) is used for obtaining results and they are expressed as Mean±SEM. A one-way analysis of variance (ANOVA), followed by Dunnett’s post hoc testis used. The statistical method applied in each analysis is described in figures presented in appendix. All the tests are done at the 5% level of significance and for this reason results are considered to be significant when their corresponding p-values are less than 0.05 (p<0.05).

RESULTS

Evaluation of granules: The various micromeritic characteristics of the granules are analyzed and showed that the choice of wet granulation method imparted good attributes on granules to formulate good quality tablets. The values of micromeritic parameters with experimental considerations according to USP29-NF24 are shown in Table 1.

The average value of angle of repose and SD, 33.48±0.3863° showed good flow property of granules that resulted in uniform and rapid filling of dies cavities by granulates during tableting. It is ensured by uniformity of tablet’s weight shown in Table 2. Hausner’s ratio of 1.16±0.006 and Carr’s index of 14.08±0.108% are estimated by using values of bulk and tapped densities, respectively.

Table 1: Micromeritics parameters of granules
Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Values are Mean±SD of triplicate analyses

Table 2: Evaluation of quality of tablets
Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Values are Mean±SD of triplicate analyses

Evaluation of prepared tablets: The quality parameters, specifications of quality target according to USP29-NF24 and observed outcomes of the compressed tablet, paracetamol (500 mg) and ibuprofen (150 mg) are shown in Table 2.

The prepared caplet shape tablets are white, smooth film coated without objectionable odor with average and SD values of thickness: 6.53±0.0048, length: 16.55±0.0063 and width: 8.33±0.007, respectively. Weight variations among all tabletsare obtained and found 846.45±1.442 mg for 10 tablets which is within the range of pharmacopoeial limits and meet the standard specifications. The average hardness of 10 tablets is found 5.62±0.2821 kg as hardness measures the compactness and structural integrity of a tablet under conditions of storage, transportation and handling before usage and according to USP24-NF-24, the hardness for film coated tablet is 4-10 kg which is compatible. The friability is determined and it is 0.165±0.0115%. The friability results are also less than 1%, which meet the standard specifications and show efficiency of formulation development. The average disintegration time of the prepared six tablets is 48±0.89 sec which lie within the specified official limits showing that disintegration time of active ingredients of tablets is not impaired and the tablets disintegrated fast enough for rapid dissolution. The dissolution profile of the combined paracetamol 500 mg and ibuprofen 150 mg tablets is evaluated as the percentage of drug released at 5 min interval for 1 h shown in Table 3. The in vitro drug release studies show that approximately 50% of the drug is released from the formulated tablet within 20 min tes and within 1 h, almost 100% of the drug is released. The assay testis conducted and the results show the presence of active components, paracetamol-112.19% and ibuprofen-101.86%. As according to the pharmacopoeial specification, drug content in tablet should be ±15% of label claim, so the new product meet this criterion. This is an important quality parameter to ensure the quality of product and safety of patients and an indication that the formulation process involved in this study is good.

Table 3: Percentage of drug released at 5 min interval from the tablets
Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh

The chromatogram and data from HPLC of standard paracetamol (500 mg) and ibuprofen (150 mg) obtained for drug content or assay determination are given in Fig. 1 and the chromatogram and data from HPLC of test sample of paracetamol (500 mg) and ibuprofen (150 mg) obtained for drug content or assay determination are given in Fig. 2. From the chromatogram and data obtained by HPLC system, the parameters are analyzed and it is found that the peak of the paracetamol and ibuprofen are sharp. The average retention time with Relative Standard Deviation (RSD) of paracetamol and ibuprofen are 4.600±0.000 and 12.398±0.000, respectively and individual retention times are very close to each other. Areas Under the Curves (AUC) are also close among them and the concentration of the paracetamol and ibuprofen is determined from the values of AUC. The limit for RSD is 2±0.1% and the RSD of assay meets the specification. The potency of paracetamol (500 mg) and ibuprofen (150 mg) in formulated tablets for six samples is shown in Fig. 3. The average potency is 98.57% for paracetamol and 102.91% for ibuprofen. It also meets the specification as the potency should be within the range of 90.0-110.0%. As potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity, so the combined tablet will give proper therapeutic effect.

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 1: Chromatogram and data from HPLC of standard paracetamol (500 mg) and ibuprofen (150 mg) obtained for assay test

The chromatogram and data from HPLC of standard paracetamol (500 mg) and ibuprofen (150 mg) obtained for potency determination are given in Fig. 4 and the chromatogram and HPLC data of test sample of paracetamol (500 mg) and ibuprofen (150 mg) obtained for potency determination are given in Fig. 5. From the chromatogram and data of potency test obtained by HPLC system, the parameters are analyzed and it is found that the peak of paracetamol and ibuprofen are sharp. The average retention time with RSD of paracetamol and ibuprofen are 4.600±0.000 and 11.600±0.000, respectively during potency determination and individual retention times are very close to each other. The AUCs are also close among them and the concentration of the paracetamol and ibuprofen is determined from the values of AUC. In potency determination, the percentage RSD of AUCs is 1.316% for paracetamol and 2.546% for ibuprofen. The limit for RSD is 2±0.1%. Perhaps, the deviation of RSD of ibuprofen occurred due to working error. There are not much differences in results observed in size, shape, color, hardness, friability, in vitro drug release pattern, disintegration time, drug content uniformity and before and after the storage period at room temperature and at ambient humidity, but at temperature 40°C/75% RH in a humidity chamber there is a slight change in color of the tablets and small differences in the results of quality parameters. This has been happened due to loss of moisture. This indicates that the formulation is fairly stable at both storage conditions.

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 2: Chromatogram and data from HPLC of test sample of paracetamol (500 mg) and ibuprofen (150 mg) obtained assay test

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 3: Graphical representation of potency of paracetamol (500 mg) and ibuprofen (150 mg) in formulated tablets for six samples

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 4:Chromatogram and data from HPLC of standard paracetamol (500 mg) and ibuprofen (150 mg) obtained for potency determination

Table 4: Analgesic activity by acetic acid induced writhing in Swiss Albino mice
Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Data were presented as Mean±SEM, n = 10 in each group, p<0.05 compared to pain induced control group and analyzed by using one-way ANOVA followed by Dunnett’s test

Determination of analgesic activity of the tablets: Analgesic activity of paracetamol (500 mg) and ibuprofen (150 mg) (Test) in combination and paracetamol (500 mg) alone (Standard) are determined and compared with the only pain induced group (Control) by conducting acetic acid induced writhing test in mice. Analgesic activity by acetic acid induced writhing is given in Table 4. The effects of paracetamol alone and in combination with ibuprofen in acetic acid induced writhing or pain in mice and comparison with the control group are given in Fig. 6. The percentage inhibition of paracetamolis 50.52% and for paracetamol and ibuprofen in combination was 75.19% as graphically shown in Fig. 7.

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 5:Chromatogram and data from HPLC of test sample paracetamol (500 mg) and ibuprofen (150 mg) obtained for potency determination

DISCUSSION

Paracetamol demonstrated significant efficacy of analgesia with the comparison to that of ibuprofen but the overall phenomenon was that the combined formulated drug implicated superior analgesic effect for prospective pain management. Although, the analgesic effect of both paracetamol and NSAIDs depends on the type of performing surgery. The present study showed that the combination of paracetamol and ibuprofen (NSAID) exerts strong analgesic efficacy weather they are used either alone.

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 6:
Effects of paracetamol alone and in combination with ibuprofen in acetic acid induced pain in mice and compared with control. Data were presented as Mean±SEM, n = 10 in each group, *p<0.05 compared to pain induced control group and analyzed by using one-way ANOVA followed by Dunnett’s test

Image for - Combined Paracetamol and Ibuprofen for the Study of Analgesic Activity of Newly Formulated Dose in Prospective Pain Management in Bangladesh
Fig. 7:
Graphical presentation of percentage inhibition in acetic acid induced writhing test in mice [Control-no drug, standard-paracetamol (7.15 mg kg–1) and test-paracetamol and ibuprofen (9.3 mg kg–1)]

Paracetamol was known to be found an aniline analgesics class of drug39. Previously a study conducted and found that best tablet properties were obtained with coated paracetamol and exhibits improved flowability and adequate compressibility. Furthermore coated paracetamol in combination with both investigated superdisintegrants shows faster disintegration times and dissolution rates in comparison to paracetamol of direct compression. With regards to results, coating of paracetamol particles has a positive effect on manufacturing of tablets with immediate release40. Paracetamol is prescribed to relieve pain alone the reduction of fever whose chemical structure is known as an N-acetyl-p-aminophenol. The Non-Steroidal Anti-Inflammatory Drug (NSAIDs) ibuprofen is known as a (±)-2-(p- isobutyl phenyl) propionic acid which is prescribed to relieve fever, pain and inflammation41. Perioli et al.42 conducted a study to improve FURO biopharmaceutical properties by its formulation in a new solid oral dosage form. The result indicated that the solid oral dosage form proposed represents an interesting tool to improve FURO biopharmaceutical properties because of the in vitro high and almost complete drug release observed. This means that the combination of the composite MgAl-HTlc-FURO with a suitable super disintegrant produces a synergic effect responsible for FURO release improvement. The combined (paracetamol+ibuprofen) formulated drug demonstrated significant (p<0.05) analgesia which reduced the number of writhes in mice induced by intra-peritonial injection of 1% acetic acid (0.01 mL g–1 b.wt.). The combined formulated drug seems to be found the significant analgesic effect as compared with paracetamol standard. Many expert researchers recommend that the use of combined analgesics43 in the pain management which is consistent to our conclusion. Whatever the previous study44 supported the expectation that such combined formulated drug exerts considerably less adverse effect compared to either of its component. The findings of this research study are so important, because different types of clinical studies are consistent in which the combined formulation of paracetamol with ketoprofen or diclofenac, different surgical procedures were associated with the lower pain scores than paracetamol alone10. The available clinical data of analgesia obtained from the comparison between the paracetamol/NSAIDs combination and NSAIDs alone suggested that the standard doses of paracetamol increase the efficacy of analgesia with the addition of ketoprofen, diclofenac or naproxen45. This result supports the effect of analgesia of the formulated combined drug when treated with the experimental animals. Another study was perfomed for the formulation and evaluation of quetiapine immediate release film coated. The results indicated that there were insignificant changes during studies46. Hence, the results suggest the feasibility of developing immediate release tablets consisting of quetiapine, which has an excellent tolerability profile offering high patient acceptability that may promote patient adherence to medication and an improved quality of life. Peripheral COX enzymes are the most important enzymes involved in the pain management which are inhibited by the treatment with the combined formulated drug. Interestingly, paracetamol is an important inhibitor of peripheral COX enzymes and inhibits COX enzymes strongly to relief pain47. Several studies suggested that the paracetamol is a potent inhibitor of the peripheral COX enzyme in which one of these studies reported about the preferential COX-2 inhibition in volunteers receiving 1000 mg paracetamol48. Interestingly, it can be noted that the central action site of paracetamol was considered as COX-3 and a splice variant of COX-1 but the selective interaction is found unlikely to be clinically relevant49 and the mechanism of paracetamol-induced analgesia implicates the affection in some different way on COX-1 and/or COX-250. Badawy et al.51 conducted a study which purpose was to investigate the specific mechanism by which elevated gastric pH reduces the absorption of BMS-561389, a factor Xa inhibitor and to develop a solid formulation strategy to overcome this gastric pH interaction49. The result indicated a multitier approach was successful in identifying a solid dosage form that minimizes the pH-dependent absorption of this drug candidate51. On the other hand, several research studies supported that the various types of NSAIDs addition enhance the pain relieving effect comparable to the acetaminophen alone. It is published that acetaminophen in combination with NSAIDs (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium and diclofenac potassium) is very effective for the relief of mild to moderately severe migraine pain52. Different doses of the combination of paracetamol and ibuprofen is found to provide safe superior pain relief to placebo in adult patients following third molar removal surgery in clinical practice53. Moreover, the most important evidence is that our data adds strong analgesic effect of the formulated combined drug supported that this combination is superior to ibuprofen or paracetamol alone. During study, different types of manufacturing problems were found and solved after studying and analyzing different formulations. In formulation aspects, it is important to note that the physical and chemical characteristics of newly formulated tablet can be changed from lower to higher level if different excipients are used.

CONCLUSION

The present study is aimed to formulate a combined solid dosage of paracetamol (500 mg) and ibuprofen (150 mg). The newly formulated tablets meet the compendial limit in terms of various pre-formulation and post-formulation quality parameters. The data of the present analgesic study demonstrates that paracetamolin combination with ibuprofen produces a synergistic analgesic effect. It may be noted that the doses of paracetamol and ibuprofen are small and if they are compared with those referred in the literature, it is possible to suggest that the combination of paracetamol (500 mg) and ibuprofen (150 mg) will be effective for the clinical treatment of mild to moderately severe pain such as acute migraine pain, dental pain, post-operative pain etc in prospect of Bangladesh. In addition, it is demonstrated that the effect of the combined paracetamol and ibuprofens is superior to that of either component alone. Therefore, these mixtures are viable alternativesfor clinical pain management, especially because the low doses of the components with greater efficacy may be a potential index of lower incidence of adverse effects and patient safety in long run. Further study may include modification in the development of formulation along with clinical trials in future.

ACKNOWLEDGMENT

The authors appreciate and are highly thankful to Navana Pharmaceuticals Limited, Bangladesh to provide necessary guidance and facilities during research study. The authors gratefully acknowledge Safinaj Arju Ara Alam for giving this concept.

REFERENCES

1:  Cousins, M.J., F. Brennan and D.B. Carr, 2004. Pain relief: A universal human right. Pain, 112: 1-4.
CrossRef  |  Direct Link  |  

2:  Merskey, H. and N. Bogduk, 1994. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd Edn., IASP Press, Seattle, ISBN: 9780931092053, Pages: 222

3:  Rahman, M.S., Z.A. Begum and M.K. Samad, 2007. Prescribing pattern of non-steroidal anti-inflammatory drugs at outpatient departments of teaching hospitals. Bangladesh J. Pharmacol., 2: 1-6.
CrossRef  |  Direct Link  |  

4:  Rostom, A., C. Dube, G.A. Wells, P. Tugwell and V. Welch et al., 2002. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst. Rev.
CrossRef  |  Direct Link  |  

5:  Rossi, S., 2006. Australian Medicines Handbook. Australian Medicines Handbook Pty Ltd., Adelaide, Australia, ISBN: 0-9757919-2-3

6:  Traversa, G., A.M. Walker, F.M. Ippolito, B. Caffari and L. Capurso et al., 1995. Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs. Epidemiology, 6: 49-54.
PubMed  |  Direct Link  |  

7:  Zajac, P., A. Holbrook, M.E. Super and M. Vogt, 2013. An overview: Current clinical guidelines for the evaluation, diagnosis, treatment and management of dyspepsia. Osteopathic Family Physician, 5: 79-85.
CrossRef  |  Direct Link  |  

8:  Wang, W.H., J.Q. Huang, G.F. Zheng, H.H.X. Xia and W.M. Wong et al., 2007. Effects of proton-pump inhibitors on functional dyspepsia: A meta-analysis of randomized placebo-controlled trials. Clin. Gastroenterol. Hepatol., 5: 178-185.
CrossRef  |  Direct Link  |  

9:  Merry, A.F. and I. Power, 1995. Perioperative NSAIDs: Towards greater safety. Pain Rev., 2: 268-291.
Direct Link  |  

10:  Hyllested, M., S. Jones, J.L. Pedersen and H. Kehlet, 2002. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: A qualitative review. Br. J. Anaesthesia, 88: 199-214.
CrossRef  |  Direct Link  |  

11:  Altman, R.D., 2004. A rationale for combining acetaminophen and NSAIDs for mild-to-moderate pain. Clin. Exp. Rheumatol., 22: 110-117.
PubMed  |  

12:  Dahl, V., T. Dybvik, T. Steen, A.K. Aune, E.K. Rosenlund and J.C. Ræder, 2004. Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction. Eur. J. Anaesthesiol., 21: 471-475.
CrossRef  |  Direct Link  |  

13:  Gazal, G. and I.C. Mackie, 2007. A comparison of paracetamol, ibuprofen or their combination for pain relief following extractions in children under general anaesthesia: A randomized controlled trial. Int. J. Paediatr. Dentistry, 17: 169-177.
CrossRef  |  Direct Link  |  

14:  Viitanen, H., N. Tuominen, H. Vaaraniemi, E. Nikanne and P. Annila, 2003. Analgesic efficacy of rectal acetaminophen and ibuprofen alone or in combination for paediatric day‐case adenoidectomy. Br. J. Anaesthesia, 91: 363-367.
CrossRef  |  Direct Link  |  

15:  Menhinick, K.A., J.L. Gutmann, J.D. Regan, S.E. Taylor and P.H. Buschang, 2004. The efficacy of pain control following nonsurgical root canal treatment using ibuprofen or a combination of ibuprofen and acetaminophen in a randomized, double-blind, placebo-controlled study. Int. Endodontic J., 37: 531-541.
CrossRef  |  Direct Link  |  

16:  Mitchell, A., S.V. van Zanten, K. Inglis and G. Porter, 2008. A randomized controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine after outpatient general surgery. J. Am. Coll. Surg., 206: 472-479.
CrossRef  |  Direct Link  |  

17:  Aghababian, V.R., 2010. Essentials of Emergency Medicine. 2nd Edn., Jones and Bartlett Publishers, USA., ISBN: 9781449671624, Pages: 1096

18:  Ahmad, J., 2010. Hepatology and Transplant Hepatology: A Case Based Approach. Springer, New York, ISBN: 9781441970855, Pages: 427

19:  Martindale, W., 1996. Martindale: The Extra Pharmacopoeia. 31st Edn., The Royal Pharmaceutical Society, London, UK., ISBN-13: 9780853693420, Pages: 2739

20:  Sweetman, S., 2002. Martindale: The Complete Drug Reference. 33rd Edn., Pharmaceutical Press, London, UK., ISBN-13: 9780853694991, Pages: 2483

21:  Henry, D. and P. McGettigan, 2003. Epidemiology overview of gastrointestinal and renal toxicity of NSAIDs. Int. J. Clin. Pract., 135: 43-49.
PubMed  |  

22:  IIF., 2002. NDAC meeting on risks of NSAIDs. International Ibuprofen Foundation, August 2002. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_06_international%20ibuprofen%20foundation.htm.

23:  Briggs, G.G. and R.K. Freeman, 2014. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 10th Edn., Lippincott, Williams and Wilkins Inc., Philadelphia, PA., USA., ISBN-13: 9781451190823, Pages: 1579

24:  Berlin, Jr. C.M., S.J. Yaffe and M. Ragni, 1980. Disposition of acetaminophen in milk, saliva and plasma of lactating women. Pediatr. Pharmacol., 1: 135-141.
PubMed  |  

25:  Findlay, J.W.A., R.L. DeAngelis, M.F. Kearney, R.M. Welch and J.M. Findlay, 1981. Analgesic drugs in breast milk and plasma. Clin. Pharmacol. Therapeut., 29: 625-633.
CrossRef  |  PubMed  |  Direct Link  |  

26:  Weibert, R.T., R.J. Townsend, D.G. Kaiser and A.J. Naylor, 1982. Lack of ibuprofen secretion into human milk. Clin. Pharm., 1: 457-458.
PubMed  |  

27:  Walter, K. and C. Dilger, 1997. Ibuprofen in human milk. Br. J. Clin. Pharmacol., 44: 211-212.
PubMed  |  

28:  Ito, S., A. Blajchman, M. Stephenson, C. Eliopoulos and G. Koren, 1993. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am. J. Obstet. Gynecol., 168: 1393-1399.
CrossRef  |  Direct Link  |  

29:  Merry, A.F., P.F. Swinburn, N.G. Middleton, J.L. Edwards and M.V. Calder, 1998. Tenoxicam and paracetamol-codeine combination after oral surgery: A prospective, randomized, double-blind, placebo-controlled study. Br. J. Anaesthesia, 81: 875-880.
CrossRef  |  Direct Link  |  

30:  Bailey, E., H. Worthington and P. Coulthard, 2014. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth, a Cochrane systematic review. Br. Dental J., 216: 451-455.
CrossRef  |  Direct Link  |  

31:  Merry, A.F., R.D. Gibbs, J. Edwards, G.S. Ting, C. Frampton, E. Davies and B.J. Anderson, 2010. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: A randomized controlled trial. Br. J. Anaesthesia, 104: 80-88.
CrossRef  |  Direct Link  |  

32:  Atkinson, H.C., J. Currie, J. Moodie, S. Carson and S. Evans et al., 2015. Combination paracetamol and ibuprofen for pain relief after oral surgery: A dose ranging study. Eur. J. Clin. Pharmacol., 71: 579-587.
CrossRef  |  Direct Link  |  

33:  Atkinson, H.C., 2011. Pharmaceutical composition of ibuprofen and paracetamol and methods of using the same. United States Patent Application No. US2011/0275718 A1. https://www.google.com/patents/US20080200549.

34:  Atkinson, H.C., 2012. A combination composition comprising ibuprofen and paracetamol. European Patent Specification No. EP1781277 B1. https://www.google.com/patents/EP1781277B1?cl=en.

35:  Jahan, M.S., M.J. Islam, R. Begum, R. Kayesh and A. Rahman, 2014. A study of method development, validation and forced degradation for simultaneous quantification of paracetamol and ibuprofen in pharmaceutical dosage form by RP-HPLC method. Anal. Chem. Insights, 9: 75-81.
CrossRef  |  Direct Link  |  

36:  Yasmeen, Z., T. Mamatha, H. Farheen and H.K. Qureshi, 2013. Dissolution method development and validation for combination of ibuprofen and paracetamol tablets. Asian J. Pharmaceut. Clin. Res., 6: 164-168.
Direct Link  |  

37:  ICH., 1996. Stability testing: Photostability testing of new drug substances and products Q1B. ICH Harmonised Tripartite Guideline, Current Step 4 Version, November 6, 1996. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1B/Step4/Q1B_Guideline.pdf.

38:  Hayashi, G. and A.E. Takemori, 1971. The type of analgesic-receptor interaction involved in certain analgesic assays. Eur. J. Pharmacol., 16: 63-66.
CrossRef  |  Direct Link  |  

39:  Bertolini, A., A. Ferrari, A. Ottani, S. Guerzoni, R. Tacchi and S. Leone, 2006. Paracetamol: New vistas of an old drug. CNS Drug Rev., 12: 250-275.
CrossRef  |  Direct Link  |  

40:  Govedarica, B., R. Injac, R. Dreu and S. Srcic, 2011. Formulation and evaluation of immediate release tablets with different types of paracetamol powders prepared by direct compression. Afr. J. Pharm. Pharmacol., 5: 31-41.
CrossRef  |  Direct Link  |  

41:  Sweetman, S., 2009. Martindale: The Complete Drug Reference. 36th Edn., Pharmaceutical Press, London, UK., ISBN-13: 978-0853698425, Pages: 3712

42:  Perioli, L., G. D'Alba and C. Pagano, 2012. New oral solid dosage form for furosemide oral administration. Eur. J. Pharmaceut. Biopharmaceut., 80: 621-629.
CrossRef  |  Direct Link  |  

43:  Ong, C.K.S. and R.A. Seymour, 2008. An evidence-based update of the use of analgesics in dentistry. Periodontology, 46: 143-164.
CrossRef  |  Direct Link  |  

44:  Makwana, S., M. Patel, B. Singh, J. Upadhyay and A. Shah, 2015. Development and validation of a stability indicating RP-UPLC method for the determination of paracetamol and ibuprofen in tablet. J. Chem. Pharmaceut. Res., 4: 1308-1315.
Direct Link  |  

45:  Seideman, P., 1993. Paracetamol in rheumatoid arthritis. Agents Actions, 44: 7-12.
PubMed  |  

46:  Das, A.K., S. Bhanja and N. Srilakshmi, 2013. Formulation and evaluation of quetiapine immediate release film coated tablets. Asian J. Pharmaceut. Clin. Res., 6: 109-114.
Direct Link  |  

47:  Boutaud, O., D.M. Aronoff, J.H. Richardson, L.J. Marnett and J.A. Oates, 2002. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthases. Proc. Natl. Acad. Sci. USA., 99: 7130-7135.
CrossRef  |  Direct Link  |  

48:  Hinz, B., O. Cheremina and K. Brune, 2008. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J., 22: 383-390.
CrossRef  |  Direct Link  |  

49:  Graham, G.G. and K.F. Scott, 2005. Mechanism of action of paracetamol. Am. J. Therapeutics, 12: 46-55.
PubMed  |  Direct Link  |  

50:  Schwab, J.M., H.J. Schluesener and S. Laufer, 2003. COX-3: Just another COX or the solitary elusive target of paracetamol? Lancet, 361: 981-982.
CrossRef  |  PubMed  |  Direct Link  |  

51:  Badawy, S.I.F., D.B. Gray, F. Zhao, D. Sun, A.E. Schuster and M.A. Hussain, 2006. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharmaceut. Res., 23: 989-996.
CrossRef  |  Direct Link  |  

52:  Becker, W.J., 2015. Acute migraine treatment in adults. Headache: J. Head Face Pain, 55: 778-793.
CrossRef  |  Direct Link  |  

53:  Atkinson, H.C., I. Stanescu, C.P. Beasley, I.I. Salem and C. Frampton, 2015. A pharmacokinetic analysis of a novel fixed dose oral combination of paracetamol and ibuprofen, with emphasis on food effect. J. Bioequivalence Bioavail., 7: 150-154.
CrossRef  |  Direct Link  |  

©  2021 Science Alert. All Rights Reserved