Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood-brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration.

Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome.

Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with anti-inflammatory drugs as celecoxib (CXB). For this, CXB-loaded PLGA microparticles (MPs) for inhaled therapy and that are able to be internalized by alveolar macrophages, were developed. MPs were prepared with 5% and 10% initial percentages of CXB (MP-C1 and MP-C2). For both systems, the mean particle size was around 5 µm, which was adequate for macrophage uptake, and the mean encapsulation efficiency was >89%. The in vitro release of CXB was prolonged for more than 40 and 70 days, respectively. The uptake of fluorescein-loaded PLGA MPs by the RAW 264.7 macrophage cell line was evidenced by flow cytometry, fluorescence microscopy and confocal microscopy. CXB-loaded PLGA MPs did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of CXB (encapsulated and in solution) was evaluated by determining the IL-1, IL-6 and TNF-α levels at 24 h and 72 h in RAW 264.7 macrophages, resulting in a higher degree of reduction in the expression of inflammatory mediators for CXB in solution. A potent degree of gene expression reduction was obtained with the developed CXB-loaded MPs.

Micro- and Nano-Systems Developed for Tolcapone in Parkinson's Disease.

To date there is no cure for Parkinson's disease (PD), a devastating neurodegenerative disorder with levodopa being the cornerstone of its treatment. In early PD, levodopa provides a smooth clinical response, but after long-term therapy many patients develop motor complications. Tolcapone (TC) is an effective adjunct in the treatment of PD but has a short elimination half-life. In our work, two new controlled delivery systems of TC consisting of biodegradable PLGA 502 (poly (D,L-lactide-co-glycolide acid) microparticles (MPs) and nanoparticles (NPs) were developed and characterized. Formulations MP-TC4 and NP-TC3 were selected for animal testing. Formulation MP-TC4, prepared with 120 mg TC and 400 mg PLGA 502, exhibited a mean encapsulation efficiency (EE) of 85.13%, and zero-order in vitro release of TC for 30 days, with around 95% of the drug released at this time. Formulation NP-TC3, prepared with 10 mg of TC and 50 mg of PLGA 502, exhibited mean EE of 56.69%, particle size of 182 nm, and controlled the release of TC for 8 days. Daily i.p. (intraperitoneal) doses of rotenone (RT, 2 mg/kg) were given to Wistar rats to induce neurodegeneration. Once established, animals received TC in saline (3 mg/kg/day) or encapsulated within formulations MP-TC4 (amount of MPs equivalent to 3 mg/kg/day TC every 14 days) and NP-TC3 (amount of NPs equivalent to 3 mg/kg/day TC every 3 days). Brain analyses of Nissl-staining, GFAP (glial fibrillary acidic protein), and TH (tyrosine hydroxylase) immunohistochemistry as well as behavioral testing (catalepsy, akinesia, swim test) showed that the best formulation was NP-TC3, which was able to revert PD-like symptoms of neurodegeneration in the animal model assayed.

Application of neurotoxin- and pesticide-induced animal models of Parkinson's disease in the evaluation of new drug delivery systems.

Parkinson's disease (PD) is the second most prevalent neuro-degenerative disease after Alzheimer´s disease. It is characterized by motor symptoms such as akinesia, bradykinesia, tremor, rigidity, and postural abnormalities, due to the loss of nigral dopaminergic neurons and a decrease in the dopa-mine contents of the caudate-putamen structures. To this date, there is no cure for the disease and available treatments are aimed at controlling the symptoms. Therefore, there is an unmet need for new treatments for PD. In the past decades, animal models of PD have been proven to be valuable tools in elucidating the nature of the pathogenic processes involved in the disease, and in designing new pharmacological approaches. Here, we review the use of neurotoxin-induced and pesticide-induced animal models of PD, specifically those induced by rotenone, paraquat, maneb, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA (6-hydroxydopamine), and their application in the development of new drug delivery systems for PD.

Antiparkinsonian Agents in Investigational Polymeric Micro- and Nano-Systems.

Parkinson's disease (PD) is a devastating neurodegenerative disease characterized by progressive destruction of dopaminergic tissue in the central nervous system (CNS). To date, there is no cure for the disease, with current pharmacological treatments aimed at controlling the symptoms. Therefore, there is an unmet need for new treatments for PD. In addition to new therapeutic options, there exists the need for improved efficiency of the existing ones, as many agents have difficulties in crossing the blood-brain barrier (BBB) to achieve therapeutic levels in the CNS or exhibit inappropriate pharmacokinetic profiles, thereby limiting their clinical benefits. To overcome these limitations, an interesting approach is the use of drug delivery systems, such as polymeric microparticles (MPs) and nanoparticles (NPs) that allow for the controlled release of the active ingredients targeting to the desired site of action, increasing the bioavailability and efficacy of treatments, as well as reducing the number of administrations and adverse effects. Here we review the polymeric micro- and nano-systems under investigation as potential new therapies for PD.

Sulfasalazine Microparticles Targeting Macrophages for the Treatment of Inflammatory Diseases Affecting the Synovial Cavity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with sulfasalazine (SSZ) extensively used for long-term treatment of both juvenile and adult RA. Its use is associated with adverse effects and toxicity due to its non-selective biodistribution. Macrophages play an important role in inflammatory processes. In order to target SSZ to macrophages in this work two microparticulate systems (MPs) are developed: SSZ-loaded PLGA MPs without and with α-tocopherol, with particle sizes lower than 5 µm and encapsulation efficiencies of 81.07 ± 11% and 63.50 ± 6.62%, respectively. Release of SSZ from MPs prepared with α-tocopherol was prolonged for 20 days. In RAW 264.7 cell macrophages MPs prepared with α-tocopherol were captured faster. Cell viability studies confirmed that SSZ-loaded MPs prepared without and with α-tocopherol did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of SSZ-loaded MPs was studied by quantifying interleukins IL-1, IL-6 and TNF-α in macrophages. All formulations produced a significant reduction of cytokine concentrations after 24 and 72 h, indicating that release of SSZ from the MPs was able to inhibit the inflammatory response induced by lipopolysaccharide (LPS). Gene expression of IL-1, IL-6 and TNF-α was decreased by SSZ-loaded MPs. SSZ-loaded MPs prepared with α-tocopherol will potentially allow increasing the residence time of SSZ in the synovial cavity, prolonging its duration of action, and reducing the adverse effects associated with its non-selective biodistribution.

Potential Active Targeting of Gatifloxacin to Macrophages by Means of Surface-Modified PLGA Microparticles Destined to Treat Tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and represents one of the leading causes of mortality worldwide due to multidrug-resistant TB (MDR-TB). In our work, a new formulation of biodegradable PLGA microparticles was developed for pulmonary administration of gatifloxacin, using a surface modifier agent to actively target alveolar macrophages thereby allowing to gain access of the drug to Mycobacterium tuberculosis. For this, rapid uptake of the particles by macrophages is beneficial. This process was evaluated with fluorescein-loaded microparticles using PLGA 502 or PLGA 502H as polymers and labrafil as surface modifier. Cell phagocytosis was studied in raw 264.7 mouse macrophage cell line after 3, 5, 24, and 48 h incubation with the microparticles. Labrafil enhanced the uptake rate of PLGA 502H microparticles by macrophages which was directly related to the modification of the polymer matrix. Gatifloxacin-loaded PLGA microparticles using PLGA 502 or PLGA 502H and labrafil were prepared. From our results, only microparticles prepared with PLGA 502H and labrafil exhibited high encapsulation efficiency (89.6 ± 0.2%), rapid phagocytosis by macrophages (3 h), and remained inside the cells for at least 48 h, thereby resulting in a suitable carrier to potentially treat MDR-TB.

Nanotechnology-based drug delivery of ropinirole for Parkinson's disease.

A new drug delivery system is developed for ropinirole (RP) for the treatment of Parkinson's disease (PD) consisting of biodegradable poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). The formulation selected was prepared with 8 mg RP and 50 mg PLGA 502. This formulation exhibited mean encapsulation efficiency of 74.8 ± 8.2%, mean particle size lower than 155 nm, the zeta potential of -14.25 ± 0.43 mV and zero-order in vitro release of RP (14.13 ± 0.17 µg/h/10 mg NPs) for 5 d. Daily doses of the neurotoxin rotenone (2 mg/kg) given i.p. to male Wistar rats induced neuronal and behavioral changes similar to those of PD. Once neurodegeneration was established (15 d) animals received RP in saline (1 mg/kg/d for 35 d) or encapsulated within PLGA NPs (amount of NPs equivalent to 1 mg/kg/d RP every 3 d for 35 d). Brain histology and immunochemistry (Nissl-staining, glial fibrillary acidic protein and tyrosine hydroxylase immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that RP-loaded PLGA NPs were able to revert PD-like symptoms of neurodegeneration in the animal model assayed.

Surface-modified gatifloxacin nanoparticles with potential for treating central nervous system tuberculosis.

A new nanocarrier is developed for the passage of gatifloxacin through the blood-brain barrier to treat central nervous system tuberculosis. Gatifloxacin nanoparticles were prepared by nanoprecipitation using poly(lactic-co-glycolic acid) (PLGA) 502 and polysorbate 80 or Labrafil as surface modifiers. The evaluation of in vivo blood-brain barrier transport was carried out in male Wistar rats using rhodamine-loaded PLGA nanoparticles prepared with and without the surface modifiers. At 30 and 60 minutes after administration, nanoparticle biodistribution into the brain (hippocampus and cortex), lungs, and liver was studied. The results obtained from the cerebral cortex and hippocampus showed that functionalization of rhodamine nanoparticles significantly increased their passage into the central nervous system. At 60 minutes, rhodamine concentrations decreased in both the lungs and the liver but were still high in the cerebral cortex. To distinguish the effect between the surfactants, gatifloxacin-loaded PLGA nanoparticles were prepared. The best results corresponded to the formulation prepared with polysorbate 80 with regard to encapsulation efficiency (28.2%), particle size (176.5 nm), and ζ-potential (-20.1 mV), thereby resulting in a promising drug delivery system to treat cerebral tuberculosis.

Efficacy of Ropinirole-Loaded PLGA Microspheres for the Reversion of Rotenone- Induced Parkinsonism.

A new controlled delivery system has been developed for ropinirole (RP) for the treatment of Parkinson´s Disease (PD) consisting in PLGA microparticles (MPs) which exhibited in vitro constant release of RP (78.23 µg/day/10 mg MPs) for 19 days. The neuroprotective effects of RP released from MPs were evaluated in SKN-AS cells after exposure to rotenone (20 µM). Cell apoptosis was significantly reduced by RP (100-120 µM). Daily doses of rotenone (2 mg/kg) given i.p. to rats induced neuronal and behavioral changes similar to those of PD. After 15 days, animals received RP in saline (1 mg/kg/day for 45 days) or as MPs at two dose levels (amount of MPs equivalent to 7.5 mg/kg or 15 mg/kg RP given on days 15 and 30). Brain immunochemistry (Nisslstaining, GFAP and TH immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that animals receiving RP either in solution or encapsulated within the MPs reverted the PD symptoms with the best results obtained in animals receiving RP microspheres at the highest dose assayed, thereby confirming the potential therapeutic interest of the new RP delivery system.

An effective novel delivery strategy of rasagiline for Parkinson's disease.

This is the first report on the efficacy of a new controlled release system developed for rasagiline mesylate (RM) in a rotenone-induced rat model of Parkinson's disease (PD). PLGA microspheres in vitro released RM at a constant rate of 62.3 µg/day for two weeks. Intraperitoneal injection of rotenone (2 mg/kg/day) to Wistar rats produced typical PD symptoms. Catalepsy, akinesia and swim tests outcomes in animals receiving RM either in solution or within microspheres showed a reversal in descent latency when compared to rotenone-treated animals, being this reversal specially pronounced in animals receiving RM microspheres (dose equivalent to 1 mg/kg/day RM injected i.p. every 15 days). Nissl-staining of brain sections showed selective degeneration of the substantia nigra (SNc) dopaminergic neurons in rotenone-treated animals which was markedly reverted by RM microspheres. PET/CT with (18)F-DG resulted in mean increases of accumulation of radiotracer in striatum and SNc of around 40% in animals treated with RM microspheres which also had significant beneficial effects on Bcl-2, Bax, TNF-α mRNA and SOD2 levels as detected by real-time RT-PCR. Our results confirm the robust effect achieved by the new controlled release system developed for RM which exhibited better in vivo efficacy than RM given in solution.

Compatibility and stability of ternary admixtures of tramadol, haloperidol, and hyoscine N-butyl bromide: retrospective clinical evaluation.

BACKGROUND: Combination of drugs for subcutaneous infusion is common practice in palliative medicine, however, there is no information pertaining to the compatibility and stability of tramadol combined in ternary admixtures and no information exists regarding its clinical performance. METHODS: Tramadol hydrochloride, haloperidol lactate, and hyoscine N-butyl bromide have been examined for compatibility and stability when combined in solution under conditions mimicking their potential use via subcutaneous infusion in terminal oncology patients. Concentration ranges were 8.8-33.3 mg/mL, 0.208-0.624 mg/mL, and 3.33-6.67 mg/mL for tramadol hydrochloride, haloperidol lactate, and hyoscine N-butyl bromide. With these, 27 different admixtures were prepared and stored at 25 degrees C using 0.9% saline as diluent. Quantification was performed by high-performance liquid chromatography (HPLC). The clinical performance of the admixture was retrospectively assessed in 28 terminal oncology patients exhibiting Karnofsky's indexes of 10%-20%. RESULTS: All three drugs were very stable (>92%) at 25 degrees C for 15 days. Pain was completely controlled in all patients. Fifty percent of the patients suffered from 3-5 vomiting episodes per day and of these, 75% experienced complete control of the episodes. None of the patients showed local reactions after subcutaneous administration of the admixture. RESULTS: Our results confirm the compatibility and stability of the ternary admixture and its utility in highly vulnerable patients exhibiting moderate symptoms.

Development and validation of a reverse phase liquid chromatography method for the quantification of rasagiline mesylate in biodegradable PLGA microspheres.

In the present study, a reverse phase high performance liquid chromatographic method was developed and validated for the determination of rasagiline mesylate in biodegradable microspheres. Chromatographic separation was carried out on a RP-18 column using a mobile phase consisting of acetonitrile:water (5:95, v/v) adjusted at pH 3.1. Flow rate was 1.0 ml min(-1) and UV detection at 290 nm. Acyclovir was used as the internal standard. The calibration curve was linear over the range 0.5-20.0 microg ml(-1). R.S.D. for precision was <1.8%. Accuracy ranged between 99.01% and 102.55% with a R.S.D. lower than 1.3%. LOD and LOQ were 0.07 microg ml(-1) and 0.23 microg ml(-1), respectively. The method was simple, rapid, and easy to apply, making it very suitable for routine analysis of rasagiline mesylate in biodegradable PLGA microspheres. It could be also used with reliability for the determination of the drug in other pharmaceutical dosage forms.

Tramadol and hyoscine N-butyl bromide combined in infusion solutions: compatibility and stability.

BACKGROUND: More than two-thirds of patients with metastatic cancer experience pain. Tramadol is one of the most interesting and useful weak opioids used by palliative care units to treat moderate to moderately severe pain. Relief of distressful symptoms in terminally ill patients is of prime importance; a common practice is to administer opioid analgesics in conjunction with other drugs as hyoscine N-butyl bromide, which is very useful in reducing secretions in patients with inoperable malignant bowel obstruction. The pursuit for excellence in symptom control in patients unable to take oral medication has led to the administration of medications by other routes such as the subcutaneous route. PURPOSE: The purpose of this study was to fulfill the lack of information regarding the compatibility and physical stability of tramadol hydrochloride and hyoscine N-butyl bromide combined in infusion solutions. METHODS: The stability of nine admixtures (stored in polypropylene syringes) at 4 and 25 degrees C was assessed over a period of 15 days. RESULTS: Nonstatistically significant losses of tramadol HCl and a maximum loss of 7% for hyoscine N-butyl bromide were obtained. Therefore, tramadol HCl (dose range, 100-400 mg/day) can be formulated together in saline with hyoscine N-butyl bromide (dose range 40-80 mg/day) for s.c. infusion using a 60-ml drug infuser for a duration of 7 days.

Compatibiliity and stability of furosemide and dexamethasone combined in infusion solutions.

AIM: The goal of palliative care is the achievement of the best quality of life for patients and their families. For this, the administration of drugs by subcutaneous infusion is frequently used since many patients have great difficulties in taking drugs orally and regular intramuscular injections are painful. Usually, drugs are combined in infusion solutions. The objective was therefore to study the compatibility and stability of dexamethasone sodium phosphate (CAS 2392-39-4) and sodium furosemide (CAS 54-31-9) combined in solutions destined to subcutaneous administration in palliative medicine. METHODS: Twelve different solutions were assessed during 15 days. Drug admixtures were prepared in polypropylene syringes using 0.9 % saline as diluent and stored at 4 degrees C and 25 degrees C in the dark. Initial concentrations were 3.33-10.0 mg/ ml for sodium furosemide (dose range 40-120 mg/day) and 0.33-3.33 mg/ml (dose range 4-40 mg/day) for dexamethasone sodium phosphate. Quantification of both drugs was performed by high-performance liquid chromatography. RESULTS: After 5 days of storage at both temperatures, the maximum losses obtained were lower than 10 % for both drugs. However, after 15 days, slight precipitation/turbidity was observed in all mixtures. At this time, maximum losses of 20 % were obtained for both drugs. CONCLUSION: These results confirm the stability of mixtures prepared with sodium furosemide (< or = 120 mg/day) and dexamethasone sodium phosphate (< or = 40 mg/day) for a period of 5 days and with independence of their storage at 4 degrees C or 25 degrees C.

Stability of tramadol and haloperidol for continuous subcutaneous infusion at home.

Terminally ill cancer patients commonly suffer from several symptoms at the same time, such as pain, nausea, anxiety, cognitive failure, bowel obstruction, and fatigue. To obtain optimal symptom control, the simultaneous administration of more than one drug by continuous subcutaneous (SC) infusion is often required. Tramadol is considered an effective step II agent of the World Health Organization's analgesic ladder for the control of chronic pain conditions, including neuropathic pain, and also exhibits a good safety profile. Haloperidol has been found to be very efficient in controlling agitation with or without pain, nausea and/or vomiting of central origin, intestinal obstruction, and delirium. Although the combination of tramadol and haloperidol in the same solution for SC infusion may be desirable, the physicochemical stability of this combination has not yet been documented. Therefore, our aim was to study the physicochemical stability of drug admixtures composed of tramadol hydrochloride and haloperidol lactate, which have been stored in polypropylene syringes at 4 degrees C and 25 degrees C, and assayed at 0, 5, 7, and 15 days after preparation.

Stability and compatibility of binary mixtures of morphine hydrochloride with hyoscine-n-butyl bromide.

The aim of this study was to determine the compatibility and stability of morphine hydrochloride and hyoscine-N-butyl bromide combined in solution at three different concentrations and stored in polypropylene syringes at 4 degrees C and 25 degrees C over a period of 15 days. The doses assayed were 20, 60 and 120 mg/day for morphine hydrochloride and 40, 60 and 80 mg/day for hyoscine-N-butyl bromide. These dose ranges were chosen according to daily practice. At both temperatures, all mixtures can be considered as physically compatible since no evidence of incompatibility-that is precipitation, turbidity, colour change or opacity and gas production-were observed. After 15 days of storage, the percentages of hyoscine-N-butyl bromide remaining in the drug mixtures tested ranged between 96.07% and 92.23%. At the end of the study, the percentages of morphine hydrochloride remaining in the drug mixtures were 100% at both temperatures.

Influence of medium and temperature on the hydrolysis kinetics of propacetamol hydrochloride: determination using derivative spectrophotometry.

Propacetamol hydrochloride (PRO) is a water-soluble prodrug of paracetamol (PA) which can be parenterally administered as analgesic for the treatment of postoperative pain, acute trauma, and gastric and/or intestinal disorders where oral administration is not possible. In these circumstances, PRO can be administered in physiologic or glucose solutions since it is rapidly and quantitatively hydrolyzed into PA by plasma estearases. We have studied the degradation kinetics of PRO in 5% glucose and 0.9% saline solutions at 4 degrees C and 25 degrees C (storage and room temperatures, respectively). The analytic technique used to determine PRO and PA quantitatively was first-derivative spectrophotometry. The degradation process of PRO can be best fitted to a second-order kinetics with independence of the medium used (saline or glucose solution). The hydrolysis kinetics of PRO conversion into PA depends on the temperature but not on the assay medium (saline or glucose solution). The degradation rate constants obtained for PRO were approximately 4.5 times higher at 25 degrees C than at 4 degrees C. The values of t(90%) for PRO were 3.17 h and 3.61 h at 25 degrees C, and 13.42 h and 12.36 h at 4 degrees C when the tests were performed in 5% glucose and 0.9% saline solutions, respectively.

Study of gamma-irradiation effects on aciclovir poly(D,L-lactic-co-glycolic) acid microspheres for intravitreal administration.

Gamma-irradiation effects on aciclovir poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres, with gelatin as additive, were studied. Microspheres with a 2:2:10 aciclovir:gelatin:polymer ratio were prepared by the solvent evaporation method and sterilised by gamma-irradiation at a dose of 25 kGy. Loading efficiency, morphology (particle size analysis, scanning electron microscopy (SEM)), physical chemistry (infrared (IR) absorption spectrophotometry, differential scanning calorimetry (DSC), X-ray diffraction and gel permeation chromatography (GPC)) and in vitro release assays for 73 days were performed to evaluate the sterilisation effect on microsphere characteristics. After gamma-irradiation, no surface changes were observed by SEM. Microparticle mean diameter and aciclovir loading efficiency were not affected by gamma-ray exposition. IR spectroscopy, DSC and X-ray diffraction showed no modification of the bulk properties of the microspheres or their components. The controlled release profiles of aciclovir-loaded microspheres for 73 days were not altered upon exposure to gamma-irradiation. GPC measurements showed a decrease in molecular weight of the polymer. The sterilisation method is adequate because microspheres underwent no change after exposition to gamma-irradiation. These favourable properties of the aciclovir-loaded microspheres make them a suitable system for the intravitreal treatment of herpes virus infections, in an animal model.

Compatibility of haloperidol and hyoscine-N-butyl bromide in mixtures for subcutaneous infusion to cancer patients in palliative care.

The administration of drugs by s.c. infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in s.c. infusion solutions. Unfortunately, the compatibility and stability of haloperidol and hyoscine- N-butyl bromide has not yet been determined. The objective of this study was to study the compatibility and stability of solutions containing both drugs in polypropylene syringes. Nine different solutions were assessed for up to 15 days following preparation. The solutions were prepared in polypropylene syringes with 0.9% saline as a diluent and stored at 4 degrees C and 25 degrees C. High-performance liquid chromatography was the analytical technique used to measure haloperidol and hyoscine- N-butyl bromide. The initial concentration ranges were 0.3125-1.25 mg/ml for haloperidol and 2.5-10.0 mg/ml for hyoscine- N-butyl bromide. Haloperidol was precipitated at a concentration of >/=1.25 mg/ml when it was combined with hyoscine- N-butyl bromide. Concentrations of hyoscine- N-butyl bromide lower than 10 mg/ml in mixtures with haloperidol or 0.625 mg/ml of haloperidol in mixtures with hyoscine- N-butyl bromide for s.c. infusion allow for the administration of both drugs without any significant loss after storage at 25 degrees C for periods of up to 15 days, with approximately >/=90% and 88%, respectively, of haloperidol and hyoscine- N-butyl bromide remaining. However, after storage of the mixtures for equivalent periods at 4 degrees C the losses of hyoscine- N-butyl bromide observed at the end of the study were higher than 20%, while the percentages of haloperidol remaining after 15 days at this temperature were >/=94.37%.