Chronic pain reduces patients’ life quality, affects their social and productive function in the state for a long period of time, or even for a whole lifetime. For the chronic pain treatment analgesic medications of symptomatic action are prescribed. According to international guidelines, paracetamol is one of the first line drugs. Aim – сonducting an assortment analysis of pharmaceutical medicines of Ukraine that can be used for the treatment of сhronic pain. Search for combined analgesics with hepatoprotective activity for the treatment of сhronic pain. Information sources: State Register of Medicines of Ukraine, Compendium web site. The analysis was conducted using content analysis and marketing research. Data processing and graphical analysis were performed in MS Excel software. During the marketing analysis of the registered in Ukraine medicines that can be used for mild and moderate сhronic pain treatment, the international non-proprietary names, listed in the national protocol of Ukraine, were selected. According to the ATC classification, these are groups N02B (non-narcotic analgesics) and M01A (non-steroidal anti-inflammatory and antirheumatic agents). N02B group has 245 registered drugs, 53.06% of which are produced domestically. Group M01A consists of 392 trade names that can be used for сhronic pain therapy. The ratio of Ukrainian manufacturers is only 39.80%, while foreign ones – 60.20%. For the treatment of сhronic pain tablet or capsule dosage forms are used. The market of analgesic products of Ukraine that can be used for сhronic pain therapy has been analyzed. It is established that the pharmaceutical market of Ukraine is import-dependent and promising for domestic enterprises. In Ukraine there are no drugs with paracetamol in combination with hepatoprotective ingredients and preparations directed exceptionally to сhronic pain treatment. In addition, there are practically no drugs of this direction in modern dosage forms (orally disintegrating tablets, soluble tablets, modified-release tablets, etc.) that improve patient compliance. All this is the basis for increasing the assortment of products in modern dosage forms.
The aim. Experimental selection of paracetamol and N-acetyl-D-glucosamine (NAG) ratio and combined dose and bioavailability study of the pharmaceutical composition and active pharmaceutical ingredient (API) in the model of cell biomembranes. Materials and methods. The following substances were used: paracetamol, Actimask Acetaminophen (gelatin-coated paracetamol), and NAG. For pharmacological studies were used laboratory rats, which received test objects intragastrically. The study was performed on the model of inflammatory hyperalgesia according to the Randall-Selitto method. The values of pain threshold before and after pathology induction were established. For biopharmaceutical studies, dry L-α-dimyristoylphosphatidylcholine purchased from Avanti Polar Lipids (purity 99.9 %) was used, hydrated with an appropriate amount of double-distilled water to obtain 70 % wt./wt. water dispersion. Differential scanning calorimetry (DSC) studies were performed employing DSC 1 microcalorimeter (Mettler Toledo). Pharmaceuticals investigated were placed on the bottom of a crucible, then a proper amount of the lipid membrane was added and this moment was taken as the time reference point (t=0). Then a crucible was sealed with a lid and a sample was undergone consecutive temperature scans, heating from 0 to 35 ºC at a scanning rate of 2 ºC/min. The procedure was repeated until no more changes in DSC profiles were observed, i.e. system equilibrium was reached. Results. It has been experimentally proven that the combination of paracetamol and NAG in the ratio of 4:1 showed better analgesic efficacy. The dose of active ingredients was determined to be 50 mg/kg by the sum of API. The active interaction of paracetamol with the bilayer of biomembranes was established and it was determined that Actimask has a worse rate of penetration into the membrane due to the coating of paracetamol with a gelatin shell. NAG didn't significantly affect the rate of penetration of Actimask through the bilayer of membranes, but the auxiliary components of the tablet mixture significantly improved the rate and completeness of penetration of paracetamol through the bilayer of biomembranes. Conclusions. The study found the most effective ratio between paracetamol and NAG in the composition, which is 4:1. The next step was to determine the dose of API, which is 50 mg/kg of the sum of active substances. It has been determined that paracetamol has good permeability through the bilayer of biomembranes, and the tablet mass significantly improves the permeability of paracetamol
One of the main problems in the production of tablets, which has significant negative consequences, is the segregation of the tablet mixture leading to inhomogeneity of dosage units, material losses in the manufacturing process and improperness of the specified pharmaceutical technical characteristics of the mixture. The aim of the research. This work aims at the pharmaceutical technical study of the substances N-acetyl-D-glucosamine and Actimask® Acetaminophen and determination the uniformity of the powder mixture of active pharmaceutical ingredients (APIs) to predict the optimal technology for obtaining a pharmaceutical formulation with the acceptable properties. Materials and methods. N-acetyl-D-glucosamine (Zhejiang Candorly Pharmaceutical, China) and Actimask® Acetaminophen (SpiPharma, USA) were used. Scanning probe microscope Solver P47N-PRO ("NT-MDT", Russia), optical microscope, flowability tester VP-12A, laser diffraction particle size analyzer SALD-2201 ("Shimadzu", Japan), liquid chromatograph Agilent 1260 Infinity II with Diode Array Detector (Agilent Technologies, USA), spectrophotometers Shimadzu UV-1800 ("Shimadzu", Japan) were used. The study of API pharmaceutical technical properties (microscopic characteristics, moisture absorption capacity, flowability, bulk volume and tapped volume, particle size distribution by sieve analysis and laser diffraction), as well as vibration simulation and following chromatographic study were carried out in this work. Results and discussion. The shape of the particles N-acetyl-D-glucosamine and Actimask® Acetaminophen, which was determined by microscopic analysis, demonstrated the possibility of N-acetyl-D-glucosamine particles to stick to Actimask® Acetaminophen ones. The experimental study allowed to reveal the hygroscopicity of both APIs; poor flowability, unsatisfactory Hausner ratio, and Carr index for N-acetyl-D-glucosamine; excellent flowability, Hausner ratio, and Carr index for Actimask®. Vibration caused segregation of the powder mixture. It was found that all layers do not meet the requirements and an excessive content of Actimask® is registered, which indicates the stratification of the powder mixture. Conclusions. The physical properties of the substances were determined and found to have significant differences in their particle size distribution. Segregation of the mixture after vibration was confirmed by laser diffraction and assay analysis. In order to solve the segregation problem, the granulation of N-acetyl-D-glucosamine may be proposed.
Aim. The choice of the qualitative and quantitative composition of excipients to provide the required mechanical strength and disintegration time when developing a pharmaceutical composition in the form of orally disintegrating tablets (ODT) based on paracetamol and N-acetyl-D-glucosamine. Materials and methods. The study object was pharmaceutically accepted excipients used in the pharmaceutical development of solid dosage forms. To conduct the statistical analysis of experimental data, a Minitab® 19.1.1 software was used. Results and discussion. The excipients (povidone of different brands, copovidone, crospovidone of different brands, croscarmellose) used when developing ODT were considered, and it was determined that copovidone and crospovidone type A showed the most optimal quality indicators of the composition. It was found that the particle sizeof crospovidone and the route of its introduction affected the rate of disintegration in the aqueous medium. Using the method of mathematical prediction the optimal content of excipients in the composition and the experimental confirmation ofthe quality indicators of the mixture selected to create ODT were determined. Conclusions. Excipients used in the development of ODT have been considered, and the excipients exhibiting the best quality indicators of the compositions have been found. Both the influence of the particle size of crospovidone, and the route of its administration have been determined. The optimal content of excipients in the composition and their experimental confirmation have been determined due to mathematical prediction.
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