Co-Spray Drying of Paracetamol and Propyphenazone with Polymeric Binders for Enabling Compaction and Stability Improvement in a Combination Tablet

Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT–PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength.

P063 SystmOne clinical reporting to identify high-risk rheumatology patients for shielding

Background/Aims At the start of the COVID-19 pandemic, shielding guidance was issued by Public Health England with a risk stratification guide developed by the BSR to assist with patient identification. At BTHFT we benefited with all GP practices in the region using TPP SystmOne (S1) for medical records. We describe how we used S1 to help identify high risk patients under our care. Methods We did not appreciate the full extent we could use S1 to identify patients in our initial shielding identification process. As such, we reviewed notes of patients on biologic prescriptions and SC MTX from Homecare prescription lists. To capture patients on high dose prednisolone, we identified patients with a recent diagnosis of GCA and patients with recent prescriptions of > 20mg prednisolone through pharmacy records. On recognising the ability of S1 to identify patients that had glucocorticoid exposure through primary care and/or on cDMARDS we used S1 reporting mechanisms to identify these patients. Clinical record sharing enabled BTHFT’s rheumatology department to access S1 for all patients under their care. S1’s clinical reporting function was used to search for patients within at least one of the following cohorts before being combined in a single cohort of ‘at risk’ patients (heart, lung or kidney disease, ≥70 years, diabetes or hypertension [including pulmonary artery hypertension]). Reports were created for patients on any DMARD issued within primary care within the previous 12 weeks. High dose steroid use was more challenging to demonstrate, but a report was devised to include all patients with an issued prescription for prednisolone 5mg tablets within the preceding 8 weeks (for any reason). An additional report was created for patients with a rheumatological diagnosis co-existing with an interstitial lung disease. Using S1's report joining function, the different drugs and ‘at risk’ cohorts were combined to provide an accurate list of patients with features increasing their vulnerability to COVID-19. This list was easily modifiable and searches were re-run to update lists once inclusion on the shielding list was updated. Results Patients meeting the criteria for shielding were then advised in writing including signposting to BTHFT’s rheumatology website and helpline for further information if required. By searching for all prednisolone prescriptions, this would have included patients given prednisolone for other reasons. 5mg tablet strength ensured patients on low dose were excluded, but we recognise some patients were likely over-recruited into this cohort. Conclusion We can update our searching methods to easily include patients on biologics and SC MTX by some additional bulk coding in preparation for future shielding specifications thereby bypassing the need to review individual notes for patients. We were able to achieve an accurate shielding list in a relatively short space of time to reduce patient risk. Disclosure D. Kirby: None. K. Nadesalingam: None.

Particle size, compaction characteristic and tablet strength of spray-dried fermented jackfruit pulp - microcrystalline cellulose binary powder mixture

The tableting properties for fermented spray dried jackfruit (FJP) and microcrystalline cellulose (MCC) powders were studied. 25% FJP + 75% MCC, 50% FJP + 50% MCC and 75% FJP + 25% MCC binary powder mixtures were compacted into tablet form at various compaction pressures ranging from 15.1 to 73.8 MPa. The properties were compared to pure FJP and MCC tablets. The addition of MCC resulted in a higher particle size and the increased in the plastic work of the tablet. The best ratio of FJP-MCC binary tablet was found to be at 25% FJP + 75% MCC where the tablet showed the highest tensile strength. In conclusion, the addition of MCC to FJP improved the compaction characteristics and the tablet mechanical strength.

Compaction behaviour of mannitol-cocoa powder mixtures and their resulting tablet strength and disintegration characteristics

Cocoa powder is an important ingredient in the confectionery industry and, mannitol is an alternative sugar alcohol. In this work, mannitol powder was mixed with cocoa powder and compacted into tablet form via the uniaxial die compaction process. The frictional, compaction, tablet mechanical and disintegration properties were studied due to their importance in characterizing the behaviour of the tablets during processing and its final product characteristics at varying mannitol contents. The composition of mannitol in the mannitol-cocoa tablet varied at 95% w/w, 50% w/w and 5% w/w, while pure 100% w/w mannitol and cocoa tablets were set as controls. The compaction pressures used in making the tablets varied at 37.67 MPa, 75.34 MPa, 113.01 MPa, 150.68 MPa and 188.35 MPa. The compaction behaviour of the powder during the compaction process was evaluated using the plastic work and the maximum ejection stress values. The tablet strength was determined using the tensile strength method and tablet disintegration study was also conducted. The results showed that the increase in the compaction pressures increased the plastic work, maximum ejection pressure, tablet strength and also its disintegration time. The tablet formed having 95% w/w mannitol composition exhibited the highest plastic work value of 10.32±0.01 J, highest maximum ejection pressure value of 4.4±0.06 MPa, highest tensile strength value of 1.06±0.04 MPa and shortest disintegration time of 171±51 s amongst the three different mannitol compositions studied. Meanwhile, the effects of mannitol composition in the tablet on these observed responses were also dependent upon the compaction pressures used during tablet formation. In conclusion, the addition of mannitol improved the tablet strength and shorten the disintegration time in the experimental range employed in this study.

Characterizing the Effect of Opioid Tablet Strength on Post-Operative Opioid Consumption Following ACL Reconstruction

Objectives: Prescription opioid abuse continues to be a national crisis in the United States. Orthopaedic surgeons contribute significantly to this crisis, prescribing nearly a tenth of annual opioid prescriptions. With Anterior Cruciate Ligament (ACL) reconstruction being a common orthopaedic procedure performed at high volumes, understanding how physician opioid prescribing practices affects patient post-operative opioid utilization is of critical importance to curbing the orthopaedic contribution to the opioid epidemic. We aimed to assess how opioid tablet strength affects post-operative opioid consumption following ACL reconstruction. We hypothesized that prescribing a lower strength opioid tablet would not adversely influence post-operative pain or increase opioid consumption Methods: All data was collected prospectively from patients undergoing ACL reconstruction at a single academic ambulatory surgery center.All patients received the same peri-operative pain management protocol, which consisted of an adductor canal block at the time of surgery, Naprosyn 500 mg to be taken as needed, and pre-operative opioid education that outlined safe opioid use practice. Percocet was prescribed at two dosages in a consecutive fashion. Between March 2018 to October 2018, patients received Percocet at a strength of 7.5 mg (7.5 mg Oxycodone/325 Acetaminophen). From November 2018 to May 2019, patients received prescriptions at a dose of 5 mg. At the first post-operative clinic visit, patients completed a survey describing the quantity of opioid tablets consumed, days of postoperative opioid use, and opioid-related adverse effects. In addition, patients used a smart-phone application to assess post-operative pain on a numeric rating scale from post-operative day (POD) 1 to POD 6. Results: 148 patients were prospectively enrolled. 78 (51.3%) received Percocet at a strength of 7.5 mg per tablet and 69 (46.9%)received Percocet at a strength of 5 mg. The median age was 23 years (interquartile range: 18-36) and 49.7% were female. The 7.5 mg cohort took an average of 12.4 tablets (±7.0), while the 5 mg cohort took an average of 8.6 (±7.4) tablets, a 3.7 tablet decrease (p=0.002). Both cohorts consumed opioids for the same amount of post-operative days (5mg cohort: 3.1 days, 7.5mg cohort: 3.5 days; p=0.289). The incidence of opioid related side effect were equivalent between the 5 mg and 7.5 mg cohorts, which included constipation (34.8% and 34.6%, p=0.983), euphoria (5.8% v. 10.3%, p=0.324), nausea/vomiting (13.0% v. 16.7%, p=0.539), fatigue (2.9% v. 6.4%, p0.319), and pruritus (2.9% v. 5.1%, p=0.495). There was no difference in post-operative numeric pain scores in the 5 mg vs. the 7.5 mg cohort (POD 1: 5.7 ±1.9 vs. 5.4 ± 2.0, p=0.633; POD 6: 3.3 ± 2.1 vs. 2.9 ± 1.8, p=0.726). Conclusion: Prescribing a lower strength of oxycodone after ACL reconstruction did not increase pain scores or opioid consumption.This suggests that it is possible to achieve similar pain control while lowering the total opioid prescribed. These finding support future research focusing on optimizing pain control at minimal opioid doses.

Pharmacokinetics of a 1,000 mg Disintegrating Aspirin Tablet Formulation

Migraine is a global disorder and considerably affecting people`s quality of life. Treatments include nonsteroidal anti-inflammatory drugs-containing medicinal products among whom acetylsalicylic acid-containing Aspirin® has been proven effectively to relief migraine headache. Early treatment is recommended for patients with migraine attacks. A requirement for early onset of action includes tablet disintegration and consequent active ingredient dissolution and absorption. The bioavailability of a new quickly disintegrating 1,000 mg aspirin formulation has been investigated in a bioequivalence study versus a marketed Aspirin® formulation with clinically demonstrated early onset of action. The new formulation has a tablet strength (1,000 mg) and time to maximum plasma concentration (mean 21.6 minutes) providing upside for people requiring treatment of migraine headache

Real-World Experience With Higher-Than-Recommended Doses of Lamivudine in Patients With Varying Degrees of Renal Impairment

Background Although nucleoside reverse transcriptase inhibitors have been associated with lactic acidosis, lamivudine (3TC) has not been reported to have an increased risk with elevated concentrations. Therefore, some recommend that the lowest tablet strength of 3TC be considered in patients with kidney disease to avoid the inconvenience of liquid formations. Our institution avoids dose-adjusting 3TC until creatinine clearance (CrCl) <30 mL/min and uses 100–150-mg tablets daily in hemodialysis. The aim of this study was to describe the use of higher-than-recommended doses of 3TC in a real-world setting. Methods Blood samples were collected before and 0.5–1.5 hours after 3TC administration in HIV+ adults. Predose (Cmin) and postdose (Cmax) samples were measured by high-performance liquid chromatography. Physiologically based pharmacokinetic modeling was utilized to simulate areas under the curve (AUCs) and profiles by CrCl. Lactic acid levels and patient-reported adverse events were obtained to monitor for safety, and viral suppression was assessed for efficacy. Results Thirty-four patients with varying degrees of renal function were enrolled. Observed 3TC Cmax values were comparable among CrCl cohorts. Simulated 3TC AUC values in patients with CrCl 30–49, 15–29, and 0–15 mL/min were consistent with historical data, and fold-errors were between 0.5 and 2.0. All lactic acid levels were within normal limits, and no adverse effects were reported. Conclusions This study is the first to describe the use of higher-than-recommended doses of 3TC in a real-world setting. 3TC was well tolerated across all levels of renal function. These results can guide providers in their selection of higher 3TC dosing in select patients with renal dysfunction to maximize adherence.