ABSTRACT
The hypothesis of the study was that (1) 3D printed drug delivery systems (DDS) could be characterized in situ during drug release using NMR/MRI techniques in terms of mass transport phenomena description (interfacial phenomena), particularly for systems dealing with two mobile phases (e.g., water and low molecular weight liquid polymer); (2) consequently, it could be possible to deduce how these interfacial mass transport phenomena influence functional properties of 3D printed DDS. Matrix drug delivery systems, prepared using masked stereolithography (MSLA), containing poly(ethylene glycol) diacrylate (PEGDA) and low molecular weight polyethylene glycol (PEG) with ropinirole hydrochloride (RH) were studied as example formulations. The PEGDA to PEG (mobile phase) concentration ratio influenced drug release. It was reflected in spatiotemporal changes in parametric T2 relaxation time (T2) and amplitude (A) images obtained using magnetic resonance imaging (MRI) and T1-T2 relaxation time correlations obtained using low-field time-domain nuclear magnetic resonance (LF TD NMR) relaxometry during incubation in water. For most of the tested formulations, two signal components related to PEG and water were assessed in the hydrated matrices by MRI relaxometry (parametric T2/A images). The PEG component faded out due to outward PEG diffusion and was gradually replaced by the water component. Both components spatially and temporally changed their parameters, reflecting evolving water-polymer interactions. The study shows that dynamic phenomena related to bidirectional mass transport can be quantified in situ using NMR and MRI techniques to gain insight into drug release mechanisms from 3D printed DDS systems.
Subject(s)
Drug Delivery Systems , Magnetic Resonance Imaging , Polyethylene Glycols , Printing, Three-Dimensional , Polyethylene Glycols/chemistry , Magnetic Resonance Imaging/methods , Drug Liberation , Indoles/chemistryABSTRACT
3D printing by selective laser sintering (SLS) of high-dose drug delivery systems using pure brittle crystalline active pharmaceutical ingredients (API) is possible but impractical. Currently used pharmaceutical grade excipients, including polymers, are primarily designed for powder compression, ensuring good mechanical properties. Using these excipients for SLS usually leads to poor mechanical properties of printed tablets (printlets). Composite printlets consisting of sintered carbon-stained polyamide (PA12) and metronidazole (Met) were manufactured by SLS to overcome the issue. The printlets were characterized using DSC and IR spectroscopy together with an assessment of mechanical properties. Functional properties of the printlets, i.e., drug release in USP3 and USP4 apparatus together with flotation assessment, were evaluated. The printlets contained 80 to 90% of Met (therapeutic dose ca. 600 mg), had hardness above 40 N (comparable with compressed tablets) and were of good quality with internal porous structure, which assured flotation. The thermal stability of the composite material and the identity of its constituents were confirmed. Elastic PA12 mesh maintained the shape and structure of the printlets during drug dissolution and flotation. Laser speed and the addition of an osmotic agent in low content influenced drug release virtually not changing composition of the printlet; time to release 80% of Met varied from 0.5 to 5 h. Composite printlets consisting of elastic insoluble PA12 mesh filled with high content of crystalline Met were manufactured by 3D SLS printing. Dissolution modification by the addition of an osmotic agent was demonstrated. The study shows the need to define the requirements for excipients dedicated to 3D printing and to search for appropriate materials for this purpose.
ABSTRACT
In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.
Subject(s)
Bosentan/chemistry , Calorimetry, Differential Scanning , Dielectric Spectroscopy , Drug Liberation , Spectroscopy, Fourier Transform Infrared , Thermogravimetry , Vitrification , X-Ray DiffractionABSTRACT
Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles' size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension's stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.
Subject(s)
Chemical Precipitation , Cilostazol/chemistry , Nanoparticles/chemistry , Sonication/methods , Ultrasonic Waves , Crystallization , Drug Compounding/methods , Excipients/chemistry , Particle Size , Solubility , Solvents/chemistry , Suspensions , TemperatureABSTRACT
This work investigated the potential of a novel formulation of eye drops containing a non-steroidal anti-inflammatory drug-choline salicylate (CS)-and hyaluronic acid (HA). Thus, these drops may exert both anti-inflammatory and regenerative activity. The experiment was conducted through the careful characterization of physicochemical properties, stability, and quality of eye drops. Moreover, microbiological analysis, as well as penetration and cytotoxic studies, were performed. The UV, HPLC-UV, and HPLC-MS/MS methods were used to determine the purity and stability of CS. The penetration rate of CS was assessed using a hydrophilic membrane and ex vivo porcine cornea model. Additionally, the cytotoxic effects were evaluated using the SIRC cell line. The interaction between HA and CS was tested using size-exclusion chromatography and IR spectrophotometry. As a result, HA increased the viscosity of the drops, which prolonged their contact with the ocular surface, thus ensuring more effective penetration of CS into the corneal structure. After long-term storage, an interaction in the pharmaceutical phase between CS and HA was observed. However, this interaction did not affect the viability of rabbit corneal cells. Our findings showed that eye drops with CS and HA, stored at 2-8 °C in light-protected conditions, met the criteria of stability and safety.
ABSTRACT
Pharmaceutical products containing non-steroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed topical formulations used for analgesic and antirheumatic properties. These drugs must overcome the skin barrier to cause a therapeutic effect. Human skin has been widely used as a model to study in vitro drug diffusion and permeation, however, it suffers from many limitations. Therefore, to perform in vitro permeation test (IVPT), we used a Strat-M® membrane with diffusion characteristics well-correlated to human skin. This study's objective was to optimize the IVPT conditions using Plackett-Burman experimental design for bio-predictive evaluation of the in vitro permeation rates of five non-steroidal anti-inflammatory drugs (diclofenac, etofenamate, ibuprofen, ketoprofen, naproxen) across Strat-M® membrane from commercial topical formulations. The Plackett-Burman factorial design was used to screen the effect of seven factors in eight runs with one additional center point. This tool allowed us to set the sensitive and discriminative IVPT final conditions that can appropriately characterize the NSAIDs formulations. The permeation rate of etofenamate (ETF) across the Strat-M® membrane was 1.7-14.8 times faster than other NSAIDs from selected semisolids but 1.6 times slower than the ETF spray formulation.
ABSTRACT
The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of T g value of co-amorphous system using the Couchman-Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability.
ABSTRACT
Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µgâh/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µgâh/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.
Subject(s)
Drug Development , Selective Serotonin Reuptake Inhibitors/administration & dosage , Trazodone/administration & dosage , Adult , Area Under Curve , Chemistry, Pharmaceutical , Cross-Over Studies , Delayed-Action Preparations/pharmacokinetics , Female , Humans , Male , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Solubility , Therapeutic Equivalency , Trazodone/pharmacokineticsABSTRACT
Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product's bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound's intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.
Subject(s)
Niacin/chemistry , Adult , Delayed-Action Preparations/chemistry , Drug Liberation , Humans , Niacin/administration & dosage , Niacin/pharmacokinetics , Tablets/chemistry , Therapeutic EquivalencyABSTRACT
SBA-16 and two modified SBA-16 type ordered mesoporous silica were used as the carriers for ibuprofen (anti-inflammatory drug) and furosemide (loop diuretic drug). Modification of the solid carrier was prepared with chitosan or N-3[(amino(poly-propylenoxy)]aminopropyltrimethoxysilane. The samples of carriers and carrier-drug loaded materials were characterized by X-ray diffraction, N2 adsorption, Fourier-transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. The release profiles of active pharmaceutical ingredients were performed in media with different pH in the USP 2 apparatus as well as in two biorelevant media (fasted state simulated gastric fluid and fasted state small intestinal fluid) in USP 4 apparatus. The loading of active substances into mesoporous materials was performed with modified immersion method. The maximum content of deposited drug in mesoporous material was close to 12.0 and 2.2 wt.% for ibuprofen and furosemide, respectively. After drug adsorption, the reduction of BET surface area, pore volume and pore diameter of non-modified and modified SBA-16 was observed, while the cubic arrays of siliceous matrix were well preserved. The release profiles of ibuprofen and furosemide loaded in mesoporous materials in media with different pH and biorelevant fasted state simulated gastric fluid and fasted state small intestinal fluid showed that the new SBA-16 type materials modify the release profiles of furosemide, increasing the dissolution rate of these substances in the medium at pH 1.2. The cytotoxicity of the materials and permeability of drugs after their loading on SBA-16 materials were evaluated on Caco-2 model. The results of our study showed that mesoporous materials did not exert cytotoxic effects and did not influence on the permeability of both active pharmaceutical ingredients in relation to pure substances.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Diuretics/administration & dosage , Drug Carriers/chemistry , Furosemide/administration & dosage , Ibuprofen/administration & dosage , Silicon Dioxide/chemistry , Amination , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Caco-2 Cells , Diuretics/chemistry , Diuretics/pharmacokinetics , Drug Liberation , Furosemide/chemistry , Furosemide/pharmacokinetics , Humans , Ibuprofen/chemistry , Ibuprofen/pharmacokinetics , Permeability , Porosity , SolubilityABSTRACT
Currently marketed drug-eluting stents are non-selective in their anti-restenotic action. New active substance introduction to polymeric stents and vascular grafts can promote early re-endothelialization, crucial in preventing implant restenosis. Additionally, managing material hydrophobicity by blending synthetic polymers limits adverse effects on bulk properties and controls active substance release. However, the influence of hydrophilic synthetic polymer on human cells in the cardiovascular system remains to be determined. In this report, effects of both poly(ε-caprolactone) (PCL) fibers hydrophilization with Pluronic P123 (P123) and cilostazol (CIL) loading were studied. Physicochemical and mechanical properties of electrospun tubular structures produced from PCL and PCL/P123 fibers with and without CIL were investigated and compared. Release profiles studies and in vitro cell proliferation assays of electrospun materials were conducted. It was found that P123 located near the surface of electrospun fibers increased the rate of CIL release. PCL formulation sustained human umbilical vein endothelial cells (HUVEC) growth for 48â¯h. Despite improved hydrophilicity, PCL/P123 formulations were found to reduce HUVEC viability. Both PCL and PCL/P123 materials reduced primary aortic smooth muscle cells (PASM) viability after 48â¯h. In PCL formulations containing CIL, drug release caused a decrease in PASM viability. P123 blending with PCL was found to be as a useful pre-fabrication technique for modulating surface hydrophobicity of electrospun materials and the release profile of incorporated active substance. The cytotoxicity of P123 was evaluated to improve the design of drug-loaded vascular grafts for cardiovascular applications.
Subject(s)
Cardiovascular System/drug effects , Cilostazol/chemistry , Drug Liberation/drug effects , Poloxalene/chemistry , Polyesters/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Hydrophobic and Hydrophilic Interactions , Muscle, Smooth, Vascular/drug effects , Particle Size , Poloxalene/pharmacology , Surface PropertiesABSTRACT
Aims After oral administration, naproxen generates several side-effects related to stomach malfunction. Undoubtedly, the enteric dosage forms with naproxen can be considered as safer. Moreover, since it has been evidenced that development and growth of colorectal cancer is related to the presence of cyclooxygenase, naproxen is investigated in terms of the tumor prevention. The aim of the present work was to formulate and evaluate the properties of novel naproxen-loaded macrobeads, made on the basis of low-acyl gellan gum and its blends with carrageenans, guar gum, cellulose sulfate, and dextran sulfates. Method Seven formulations were prepared by ionotropic gelation. The morphology of the dried beads was evaluated by scanning electron microscopy. The next step focused on Raman spectroscopy and thermal analysis of naproxen, polymers, and the beads. Next, the swelling behavior was examined in three acceptor fluids at pH = 1.2; 4.5, and 7.4. The beads were evaluated regarding naproxen content and encapsulation efficiency. The last stage of the work concerned the drug release studies. Results Addition of any other polysaccharide than gellan resulted in flattening of the beads upon drying. Differential scanning calorimetry confirmed the crystalline form of naproxen. Raman spectra showed that no apparent interactions occurred. In the acidic environment, all the beads revealed the tendency to absorb water. The beads swelled to the greatest extent at pH = 4.5. Naproxen was released from the beads at a varied rate. At pH = 7.4, the most prolonged release was observed for the beads containing carrageenans. Conclusions We have proved that blending of gellan with various polysaccharides can change the pH-dependent properties of the beads loaded with naproxen. We believe that the information enclosed in the paper will be of particular importance regarding the development and characteristics of novel oral dosage forms based on natural polymers.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anticarcinogenic Agents/chemistry , Drug Carriers/chemistry , Naproxen/chemistry , Polysaccharides, Bacterial/chemistry , Carrageenan/chemistry , Cellulose/analogs & derivatives , Cellulose/chemistry , Chemistry, Pharmaceutical/methods , Dextran Sulfate/chemistry , Drug Liberation , Galactans/chemistry , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Mannans/chemistry , Microspheres , Plant Gums/chemistryABSTRACT
PURPOSE: The study discusses the value of electrospun cilostazol-loaded (CIL) polymer structures for potential vascular implant applications. METHODS: Biodegradable polycaprolactone (PCL) fibers were produced by electrospinning on a rotating drum collector. Three different concentrations of CIL: 6.25%, 12.50% and 18.75% based on the amount of polymer, were incorporated into the fibers. The fibers were characterized by their size, shape and orientation. Materials characterization was carried out by Fourier Transformed Infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vitro drug release study was conducted using flow-through cell apparatus (USP 4). RESULTS: Three-dimensional structures characterized by fibers diameter ranging from 0.81 to 2.48 µm were in the range required for cardiovascular application. DSC and XRD confirmed the presence of CIL in the electrospun fibers. FTIR and Raman spectra confirmed CIL polymorphic form. Elastic modulus values for PCL and the CIL-loaded PCL fibers were in the range from 0.6 to 1.1 GPa. The in vitro release studies were conducted and revealed drug dissolution in combination with diffusion and polymer relaxation as mechanisms for CIL release from the polymer matrix. CONCLUSIONS: The release profile of CIL and nanomechanical properties of all formulations of PCL fibers demonstrate that the cilostazol loaded PCL fibers are an efficient delivery system for vascular implant application.
Subject(s)
Blood Vessel Prosthesis , Cilostazol/administration & dosage , Drug Delivery Systems , Platelet Aggregation Inhibitors/administration & dosage , Thrombosis/prevention & control , Atherosclerosis/surgery , Blood Vessel Prosthesis Implantation/adverse effects , Cilostazol/pharmacokinetics , Drug Compounding/methods , Drug Liberation , Humans , Platelet Aggregation Inhibitors/pharmacokinetics , Polyesters/chemistry , Thrombosis/etiologyABSTRACT
BACKGROUND: Oral administration of non-selective COX inhibitors involves the risk of serious side-effects. In the case of naproxen (NPX), the most frequent are those related to malfunctioning of the gastric mucosa. On the other hand, NPX and other NSAIDs are extensively studied in terms of colorectal cancer (CRC) prevention and inhibition, since it has been evidenced that COX-2 corresponds with the risk of the tumor occurrence and growth. Both side-effects in the stomach and possible antitumor activity of NPX justify the attempts to search for novel carriers for NPX with the site specific release in the colon. Thus, the aim of the work was to design, formulate and characterize low-acyl gellan gum (GG) macro beads as potential carriers for the delivery of NPX to the distal parts of the gastrointestinal tract. METHODS: The beads were obtained by the ionotropic gelation technique. CaCl2 solution was used as a cross-linking medium. After production, the beads were dried and used for further experiments. First, pure NPX and the beads were evaluated by Raman spectroscopy and DSC studies. The surface and morphology of the beads were analyzed by SEM. Next, the drug encapsulation efficiency and content in the beads were determined. The swelling and degradation behavior of the beads were evaluated in four simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8 and 7.4). The NPX in vitro release studies were conducted on USP I apparatus (rotating basket) at pH=7.4 and compared to the commercial enteric tablet. RESULTS: The polymer content of 0.5 % was considered as too low to obtain spherical beads in the dried form. Raman spectra confirmed that NPX did not undergo structural changes during production process. DSC studies showed that thermal decomposition at lower temperatures was observed for formulations with the lowest amount of GG. It turned out that the most important factor which determined the morphology of the beads was the amount of gellan gum in the initial mixture. The beads revealed 13.9- 39.9% of drug loading and 75.3-99.7% drug encapsulation efficiency. Swelling of the beads was pHdependent as the beads remained stable in the acidic environment but started to absorb water. In pH=7.4 after 3 hours, the beginning of the physical decomposition of the polymer matrix was observed. The drug release studies showed that in pH=7.4 the commercial tablets released 90% of the drug after 45 minutes while the amount of NPX released from pellets after the same time was 40-80%. CONCLUSION: In general, it can be stated that gellan macro beads may be regarded as suitable for site specific delivery of NPX to the colon. However, these simple to obtain beads can be potentially used as carriers for many different drugs whenever it is necessary to omit the stomach.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Naproxen/chemistry , Polysaccharides, Bacterial/chemistry , Hydrogen-Ion Concentration , Molecular Structure , Particle Size , Surface PropertiesABSTRACT
The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett-Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.
Subject(s)
Desiccation/methods , Excipients/chemistry , Tablets/chemistry , Chemistry, Pharmaceutical , Drug Liberation , Pressure , Regression Analysis , Solubility , TemperatureABSTRACT
The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10-2 M) was used as the cross-linking agent. Nine different polymer, drug and surfactant (Tween®80) mixtures were used for production of the beads. The quantitative compositions of the mixtures were generated with the application of the Design of Experiments (DoE) modulus from the STATISTICA Software. The prepared formulations revealed 7.2-27.0% of drug loading and 29.2-50.7% drug encapsulation efficiency. It turned out that 0.5% amount of gellan gum in the mixtures was not sufficient to obtain spherical beads. The morphology and surface of the dried beads were analyzed by SEM. Raman spectra confirmed that MLX did not undergo structural changes during production of the beads. The swelling behavior and degradation of the beads were evaluated in three simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8). The MLX in vitro release studies were conducted on USP apparatus IV, working in the open loop mode. The obtained results showed that MLX release from the dried beads was pH-dependent. The formulations obtained from mixtures containing 1.0 and 1.5% of gellan may be considered as oral dosage forms for MLX, intended to omit the stomach and release the drug in the distal parts of the gastrointestinal tract.
Subject(s)
Drug Carriers/pharmacokinetics , Gels/chemistry , Polysaccharides, Bacterial/administration & dosage , Thiazines/administration & dosage , Thiazines/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/pharmacokinetics , Calcium Chloride/chemistry , Chemistry, Pharmaceutical , Colorectal Neoplasms/drug therapy , Drug Carriers/chemistry , Meloxicam , Polysaccharides, Bacterial/chemistry , Thiazines/chemistry , Thiazoles/chemistryABSTRACT
Taking into account possible irritation of the skin upon contact with naproxen (NPX) crystals and lower bioavailability after administration of the suspended or ionized drug, the aim of the work was to design and characterize novel and easy-to-formulate gels with the entirely dissolved drug in the acidic form. The formulations contained ethanol, SynperonicTMPE/L 62 and Arlasolve® DMI or Transcutol®. Carbopol®940 was used as the thickener. The properties of organogels were compared with six market products. The rheological measurements included steady flow experiments and oscillatory analysis. The texture profile analysis was conducted to calculate the mechanistic parameters. The in vitro permeation studies were performed on SOTAX CE 7 smart apparatus with the application of Strat-M artificial membranes. The obtained organogels fulfilled the requirements for topical products in terms of consistency, uniformity, stability, drug dissolution and permeation. The permeation studies revealed distinct differences among the commercial hydrogels according to permeation coefficients (kP), drug flux (Jss) and average cumulative amount of NPX per area after 12 h (Q12h). The presented work clearly shows that the organogels can be proposed as an alternative for commercial products where NPX occurs in the form of crystals.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Gels/chemistry , Naproxen/administration & dosage , Skin Absorption , Administration, Cutaneous , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Drug Carriers/chemistry , Humans , Membranes, Artificial , Naproxen/pharmacokinetics , Rheology , Skin/metabolismABSTRACT
The commercially available coated tablets containing either racemic form of ofloxacin (Tarivid 200 mg, OfloHexal 200 mg and Ofloxacin-Ratiopharm 200 mg) or only levofloxacin S-(-)-isomer (Tavanic 250 mg) were examined. The aim of our study was to establish the kinetics of dissolution rate process of ofloxacin optical isomers (S-(-) and R-(+)-ofloxacin) from solid oral dosage forms using flow-through cell method (USP 4 method). The concentrations of analytes (racemic ofloxacin and its enantiomers) in the samples of tablet extracts as well as in dissolution media (0.1 M/L HCl and phosphate buffer pH 6.8) were determined by validated high performance capillary electrophoresis method. The fraction of the average dose of the individual optical isomers of ofloxacin released from the examined tablets was calculated. In the case of the OfloHexal, Ofloxacin-Ratiopharm and Tavanic it was found to be around 100% for both S-(-) and R-(+)-ofloxacin in 0.1 M/L HCI after 30 min of dissolution test. The fraction of the average dose for the Tarivid tablets was approximately 50% at the same time. A similar results were observed for the Ofloxacin-Ratiopharm and Tavanic tablets examined in phosphate buffer (average fraction about 100% after 30 min), while in the case of Tarivid and OfloHexal the averige fraction of the dose determined in a buffer pH 6.8 was 14% and 44%, respectively. There were not found any differences in the kinetics of dissolution of the S-(-)-ofloxacin and R-(+)-ofloxacin isomers within the same formulation. However, statistically significant differences were found in the dissolution of ofloxacin enantiomers between different preparations.
Subject(s)
Anti-Infective Agents/chemistry , Electrophoresis, Capillary , Levofloxacin/chemistry , Ofloxacin/chemistry , Technology, Pharmaceutical/methods , Calibration , Drug Compounding , Drug Liberation , Electrophoresis, Capillary/standards , Isomerism , Kinetics , Limit of Detection , Models, Chemical , Models, Statistical , Reference Standards , Solubility , Tablets , Technology, Pharmaceutical/standardsABSTRACT
OBJECTIVE: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets' critical quality attributes (CQA). SIGNIFICANCE: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues. METHODS: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU. RESULTS: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading. CONCLUSIONS: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API's content and uniformity when compared to industrial gravitational transfer.
Subject(s)
Drug Compounding/instrumentation , Drug Compounding/methods , Powders , Tablets , Excipients , Particle Size , Pressure , Quality Control , Technology, PharmaceuticalABSTRACT
Interactions occurring between components in the quaternary powder mixtures consisting of perindopril tert-butylamine, indapamide (active pharmaceutical ingredients), carrier substance and hydrophobic colloidal silica were examined. Two grades of lactose monohydrate: Spherolac(®) 100 and Granulac(®) 200 and two types of microcrystalline cellulose: M101D+ and Vivapur(®) 102 were used as carriers. We determined the size distribution (laser diffraction method), morphology (scanning electron microscopy) and a specific surface area of the powder particles (by nitrogen adsorption-desorption). For the determination of the surface energy of powder mixtures the method of inverse gas chromatography was applied. Investigated mixtures were characterized by surface parameters (dispersive component of surface energy, specific interactions parameters, specific surface area), work of adhesion and cohesion as well as Flory-Huggins parameter χ23('). Results obtained for all quaternary powder mixtures indicate existence of interactions between components. The strongest interactions occur for both blends with different types of microcrystalline cellulose (PM-1 and PM-4) while much weaker ones for powder mixtures with various types of lactose (PM-2 and PM-3).