Spray-congealed microparticles for drug delivery – an overview of factors influencing their production and characteristics

Introduction: In any manufacturing process, the success of producing an end product with the desired properties and yield depends on a range of factors that include the equipment, process and formulation variables. It is the interest of manufacturers and researchers to understand each manufacturing process better and ascertain the effects of various manufacturing-associated factors on the properties of the end product. Unless the manufacturing process is well understood, it would be difficult to set realistic limits for the process variables and raw material specifications to ensure consistently high-quality and reproducible end products. Over the years, spray congealing has been used to produce particulates by the food and pharmaceutical industries. The latter have used this technology to develop specialized drug delivery systems.

Areas covered: In this review, basic principles as well as advantages and disadvantages of the spray congealing process will be covered. Recent developments in spray congealing equipment, process variables and formulation variables such as the matrix material, encapsulated material and additives will also be discussed.

Expert opinion: Innovative equipment designs and formulations for spray congealing have emerged. Judicious choice of atomizers, polymers and additives is the key to achieve the desired properties of the microparticles for drug delivery.     

Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D₅₀, 1.4 to 2.5 μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D₅₀) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters.     

Investigations into the Relationship Between Drug Properties,Filling, and the Release of Drugs from Hard Gelatin Capsules Using Multivariate Statistical Analysis

Purpose. The aim of the present work is to identify complex relationships between formulation variables and dosage form properties to aid the development of hard gelatin capsules. Methods. Multivariate statistical analysis was employed based on a statistical design, which considered drug solubility, particle size and concentration, type and concentration of filler and disintegrant, and concentration of standard lubricant and glidant as the main influence factors. Both the filling properties of the formulations and the disintegration/dissolution properties of the capsule content were studied. Results. From the two multivariate statistical methods used, nonparametric canonical analysis proved to be the superior method to deal with the complex information included in the data. While the filling performance of the formulation could clearly be attributed to the formulation variables such as drug particle size, type of filler, concentration of drug and glidant, the disintegration of the capsules and the dissolution of the drugs was not strongly related to the formulation variables chosen. In this respect as a trend, the drug solubility, and the type of disintegrant and filler appear to be more important factors. Conclusions. Based on an appropriate number of experiments, organised in a statistical design, nonparametric canonical analysis can be used to identify relationships in a set of data that is grouped in influence and response variables to aid the development of a dosage form.     

An Investigation into the Dispersion Mechanisms of Ternary Dry Powder Inhaler Formulations by the Quantification of Interparticulate Forces

Purpose To investigate the dispersion mechanism(s) of ternary dry powder inhaler (DPI) formulations by comparison of the interparticulate adhesions and in vitro performance of a number of carrier–drug–fines combinations. Materials and Methods The relative levels of adhesion and cohesion between a lactose carrier and a number of drugs and fine excipients were quantified using the cohesion–adhesion balance (CAB) approach to atomic force microscopy. The in vitro performance of formulations produced using these materials was quantified and the particle size distribution of the aerosol clouds produced from these formulations determined by laser diffraction. Results Comparison between CAB ratios and formulation performance suggested that the improvement in performance brought about by the addition of fines to which the drug was more adhesive than cohesive might have been due to the formation of agglomerates of drug and fines particles. This was supported by aerosol cloud particle size data. The mechanism(s) underlying the improved performance of ternary formulations where the drug was more cohesive than adhesive to the fines was unclear. Conclusions The performance of ternary DPI formulations might be increased by the preferential formation of drug–fines agglomerates, which might be subject to greater deagglomeration forces during aerosolisation than smaller agglomerates, thus producing better formulation performance.     

Development of nanodispersion-based sildenafil metered-dose inhalers stabilized by poloxamer 188: a potential candidate for the treatment of pulmonary arterial hypertension

Objectives: This study aims to formulate nanodispersion-based sildenafil metered-dose inhalers (MDIs) by using poloxamer 188 (P188) as a stabilizer; to evaluate their stability, aerosol characteristics, cytotoxicity, and inflammatory effects; and to investigate the effects of P188 on stability and aerosol characteristics of the MDIs.

Methods: The stability and uniformity of the formulations were evaluated by high-performance liquid chromatography method. The aerosol characteristics were evaluated by the Next Generation Impactor. The cytotoxicity and inflammatory effects on respiratory epithelial cells and alveolar macrophages were evaluated by MTT assay and TNF-α, IL-1β, and NO assay, respectively.

Results: The optimal formulation was stable and well-uniform after 6?months. The fine particle fraction and mass median aerodynamic diameter (MMAD) of the formulation were 61.9%?±?2.5% and 1.69?±?0.06?µm, respectively. The formulation was found to be nontoxic to respiratory epithelial cells and did not induce the inflammatory responses of alveolar macrophages. A positive correlation between P188 concentration and MMAD of the MDIs was observed. P188 possesses an ability to prevent the growth of sildenafil citrate monohydrate crystals in the formulations.

Conclusions: The findings provided a basis for the development of sildenafil MDI as a potential candidate for the treatment of pulmonary arterial hypertension.     

星点设计-效应面法优化硝酸布康唑缓释乳膏的制备

目的 采用星点设计-效应面法对硝酸布康唑缓释乳膏的处方进行优化。方法 以液体石蜡用量(X₁)、乳化剂用量(X₂)、助乳化剂占乳化剂比例(X₃)为考察因素,以24,48,72 h的累积释放度为考察指标,分别用多元线性模型、二次多项式模型描述考察指标和3个考察因素之间的数学关系,根据模型绘制效应面图和等高线图,通过重叠等高线图确定优化处方,最后进行验证。结果 二次多项式模型比多元线性模型置信度高;根据二次多项式模型,发现 3 个考察因素和 3个考察指标之间存在可信的定量关系;优化处方各设定指标的预测值和实际值非常接近。结论 星点设计-效应面法可用于硝酸布康唑缓释乳膏的处方优化,所建模型具有良好的预测能力。     

Systemic Delivery of Cetrorelix to Rats by a New Aerosol Delivery System

Purpose. To study the pulmonary absorption and tolerability of various formulations of the decapeptide cetrorelix acetate in rats by a new aerosol delivery system (ASTA-ADS) for intratracheal application. Methods. Using the ASTA-ADS, cetrorelix liquid formulations (aqueous solutions for ultrasonic nebulization) were firstly selected and subsequently delivered as nebulized aerosol to orotracheally cannulated rats. The pharmacologic effect (decrease of testosterone serum level) of four cetrorelix formulations was determined in rats by enzyme linked immunosorbant assay, and pharmacokinetic data were determined after measurement of cetrorelix serum level by radioimmunoassay. Histological examination of the lung was performed at the end of the experiments, and in a supplementary experiment the respiratory parameters (resistance and compliance) of rats were monitored by a validated pulmonary monitoring system during the aerosol application of the same formulations. Results. After an exposure time of 5 min, the applied formulations reduced the testosterone concentration in serum to subnormal levels (1 ng/ml) over a period of 24 h. Comparing the plasma concentration after intratracheal aerosolization with data of intravenous administration, the mean calculated bioavailabilities for the four formulations using the corrected dose (delivered—exhaled amount) were between 48.4 ± 27.0% and 77.4 ± 44.0%. The histologic examination of the lungs revealed different tolerability of the various tested formulations ranging from locally intolerable to well tolerated. The measurement of the lung function parameters did not reveal any compound or formulation related changes. Conclusions. Our studies show that cetrorelix can be effectively administered as aerosol and that intratracheal aerosolization via the ASTA-ADS provides results that are well comparable to other application routes, as demonstrated by statistical comparison of the newly obtained data with previous results from intratracheal instillation of cetrorelix solutions in rats.     

Liposomal Nanoparticles Control the Uptake of Ciprofloxacin Across Respiratory Epithelia

Purpose

Liposomal ciprofloxacin nanoparticles were developed to overcome the rapid clearance of antibiotics from the lungs. The formulation was evaluated for its release profile using an air interface Calu-3 cell model and further characterised for aerosol performance and antimicrobial activity.

Methods

Liposomal and free ciprofloxacin formulations were nebulised directly onto Calu-3 bronchial epithelial cells placed in an in vitro twin-stage impinger (TSI) to assess the kinetics of release. The aerosol performance of both the liposomal and free ciprofloxacin formulation was characterised using the next generation impactor. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined and compared between formulations to evaluate the antibacterial activity.

Results

The liposomal formulation successfully controlled the release of ciprofloxacin in the cell model and showed enhanced antibacterial activity against Pseudomonas aeruginosa. In addition, the formulation displayed a respirable aerosol fraction of 70.5?±?2.03% of the emitted dose.

Conclusion

Results indicate that the in vitro TSI air interface Calu-3 model is capable of evaluating the fate of nebulised liposomal nanoparticle formulations and support the potential for inhaled liposomal ciprofloxacin to provide a promising treatment for respiratory infections.     

Skin Penetration and Mechanisms of Action in the Delivery of the D2-Agonist Rotigotine from Surfactant-Based Elastic Vesicle Formulations

Purpose. This study was performed to investigate the effect of elastic and rigid vesicles on the penetration of the D₂ dopamine agonist rotigotine across human skin and to further elucidate the mechanisms of action of the elastic vesicles. Methods. A series of rotigotine-loaded vesicles were prepared, ranging from very elastic to very rigid. The drug penetration from these vesicles across human skin was studied in vitro using flow-through diffusion cells. Micelle and buffer solutions were investigated as controls. For the most elastic vesicle composition, two additional variables were investigated. Coapplication of drug and vesicles was compared to pretreatment, and the effect of the drug entrapment efficiency was investigated. Results. The very elastic vesicle formulation L-595/PEG-8-L (50/50) gave steady-state fluxes of 214.4 ± 27.8 ng/(h · cm²). This formulation was the most effective formulation and significantly better than the rigid vesicle formulations as well as the micelle and buffer controls. However, coapplication and a high drug entrapment efficiency were essential factors for an optimal drug delivery from elastic vesicle formulations. Conclusions. Elastic vesicles are promising vehicles for transdermal drug delivery. It is essential that drug molecules are applied together with and entrapped within the vesicles themselves, suggesting that elastic vesicles act as drug carrier systems and not solely as penetration enhancers.     

Inhaled gene delivery: a formulation and delivery approach

Introduction: Gene therapy is a potential alternative to treat a number of diseases. Different hurdles are associated with aerosol gene delivery due to the susceptibility of plasmid DNA (pDNA) structure to be degraded during the aerosolization process. Different strategies have been investigated in order to protect and efficiently deliver pDNA to the lungs using non-viral vectors. To date, no successful therapy involving non-viral vectors has been marketed, highlighting the need for further investigation in this field.

Areas covered: This review is focused on the formulation and delivery of DNA to the lungs, using non-viral vectors. Aerosol gene formulations are divided according to the current delivery systems for the lung: nebulizers, dry powder inhalers and pressurized metered dose inhalers; highlighting its benefits, challenges and potential application.

Expert opinion: Successful aerosol delivery is achieved when the supercoiled DNA structure is protected during aerosolization. A formulation strategy or compounds that can protect, stabilize and efficiently transfect DNA into the cells is desired in order to produce an effective, low-cost and safe formulation. Nebulizers and dry powder inhalers are the most promising approaches to be used for aerosol delivery, due to the lower shear forces involved. In this context it is also important to highlight the importance of considering the ‘pDNA-formulation-device system’ as an integral part of the formulation development for a successful nucleic acid delivery.     

Predicting the quality of powders for inhalation from surface energy and area

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler^® (GlaxoSmithKline) or Handihaler^® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R² value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.     

The Effect of Formulation Excipients on Protein Stability and Aerosol Performance of Spray-Dried Powders of a Recombinant Humanized Anti-IgE Monoclonal Antibody1

Purpose. To study the effect of trehalose, lactose, and mannitol on the biochemical stability and aerosol performance of spray-dried powders of an anti-IgE humanized monoclonal antibody. Methods. Protein aggregation of spray-dried powders stored at various temperature and relative humidity conditions was assayed by size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. Protein glycation was determined by isoelectric focusing and affinity chromatography. Crystallization was examined by X-ray powder diffraction. Aerosol performance was assessed as the fine particle fraction (FPF) of the powders blended with coarse carrier lactose, and was determined using a multiple stage liquid impinger. Results. Soluble protein aggregation consisting of non-covalent and disulfide-linked covalent dimers and trimers occurred during storage. Aggregate was minimized by formulation with trehalose at or above a molar ratio in the range of 300:1 to 500:1 (excipient:protein). However, the powders were excessively cohesive and unsuitable for aerosol administration. Lactose had a similar stabilizing effect, and the powders exhibited acceptable aerosol performance, but protein glycation was observed during storage. The addition of mannitol also reduced aggregation, while maintaining the FPF, but only up to a molar ratio of 200:1. Further increased mannitol resulted in crystallization, which had a detrimental effect on protein stability and aerosol performance. Conclusions. Protein stability was improved by formulation with carbohydrate. However, a balance must be achieved between the addition of enough stabilizer to improve protein biochemical stability without compromising blended powder aerosol performance.     

Safety of calcipotriene and betamethasone dipropionate foam for the treatment of psoriasis

ABSTRACT

Introduction: Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated red and scaly plaques. Most patients have mild disease that is usually controlled with topical treatment. Calcipotriene 0.05% and betamethasone dipropionate 0.064% (Cal/BD) in aerosol foam (Enstilar®) is a novel formulation, which has shown promising results in terms of efficacy and safety.

Areas covered: This review evaluates the safety profile of Cal/BD aerosol foam and also the key points regarding its efficacy. A literature search was performed in PubMed in November 2019 from the start of records. Additional references were searched and retrieved manually.

Expert opnion: Cal/BD aerosol foam has proven its efficacy, safety, and tolerability in several clinical trials and real clinical practice. It has also demonstrated higher efficacy than the ointment and gel formulations of the fixed combination. It has a low incidence of adverse events; nasopharyngitis and site application pain were the most frequently reported. Moreover, it is devoid of changes in calcium homeostasis and hypothalamic-pituitary-adrenal axis. As a result of its unique formulation, it is easily spread, is rapidly absorbed, and has a rapid onset of action. These features upgrade patient’s satisfaction and they may increase adherence to topical therapy.     

A new solution-based intranasal triamcinolone acetonide formulation in patients with perennial allergic rhinitis: how does the pharmacokinetic/pharmacodynamic profile for cortisol suppression compare with an aqueous suspension-based formulation?

The present study was undertaken to describe the pharmacokinetics of a new solution-based intranasal triamcinolone acetonideformulation (Tri-Nasal) in patients with perennial allergic rhinitis and to use a pharmacokinetic/pharmacodynamic (PK/PD) simulation approach to compare the potential effects on plasma cortisol with that of an aqueous suspension-based nasal triamcinolone acetonide formulation (Nasacort AQ). Data from an open-label, randomized, three-way crossover study in patients with perennial allergic rhinitis receiving three doses (100, 200, and 400 microg) of a nasal solution-based triamcinolone acetonide formulation (Tri-Nasal) over 7 days were used to describe the pharmacokinetics of this formulation. Available literature data for a suspension-based aqueous triamcinolone acetonide formulation (Nasacort AQ) were used to describe its pharmacokinetic profile after similar single doses of 110, 220, and 440 microg. A PK/PD simulation approach was used to predict the anticipated cumulative cortisol suppression (CCS) of these two formulations. These simulations suggested a cortisol suppression of 8% to 16% for the single and steady-state doses of the solution-based product. Similar CCS estimates were predicted for equivalent doses of the aqueous suspension-based triamcinolone acetonide formulation with no difference between both formulations. Post hoc power analysis suggested that the predicted cortisol suppression is not likely to be significant for either preparation, including the clinically recommended doses of 200 and 220 microg of the solution-based and suspension-based formulations, respectively. In summary, based on the results of this PK/PD simulation, the plasma levels observed afternasal administration of the solution or the aqueous suspension are unlikely to induce a clinically relevant cortisol suppression, especially for the recommended dosing regimens of 200 and 220 microg/day.     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

The importance of interfaces in protein drug delivery – why is protein adsorption of interest in pharmaceutical formulations?

Introduction: In the area of peptide and protein drug products, interfaces are present as part of the basic liquid formulation, when freeze-dried formulations are reconstituted and when particulate delivery systems are prepared. Proteins are known to interact with these interfaces, and the effects seen are often irreversible adsorption and structural changes.

Areas covered: This review focuses on the ways in which peptides and proteins interact with surfaces and interfaces, and the effect these interactions have on the stability and safety of the active protein in pharmaceutical formulations. It illustrates, through examples, what can be determined by an adsorption study, and what can change when either the protein or the interfaces are modified. Last but not least, it addresses the value of these studies. The reader will gain an update on the basics of protein adsorption, with a focus on pharmaceutically relevant interfaces and recent advances in the field.

Expert opinion: Protein adsorption is widely studied; however, a more unified approach is still needed, especially on the adsorption of pharmaceutically relevant proteins, modified proteins and surfaces.     

Paliperidone for the treatment of schizoaffective disorder

Introduction: Schizoaffective disorder (SCA) is a complex mental illness characterized by psychosis and affective symptoms. Treatment usually involves concomitant therapy with antipsychotics, mood stabilizers, and/or antidepressants. Effective treatment must address acute symptoms, maintain long-term stability, promote recovery, and improve patient functioning.

Areas covered: Data from 3 pivotal studies evaluating the acute and maintenance treatment of SCA with paliperidone are reviewed. Two formulations of paliperidone have been studied for these indications: an extended-release oral formulation (NCT00397033, NCT00412373) and long-acting injectable once-monthly paliperidone palmitate (NCT01193153). The reported effects of these formulations on psychotic, depressive, and manic symptoms are discussed.

Expert opinion: Both formulations were found to be safe and effective for the acute and maintenance treatment of SCA. Of critical importance for this treatment population is that rapid improvement was seen in all major symptoms of SCA, including psychosis, depression, and mania. Mediation analyses suggest that the known antipsychotic effects of paliperidone occur independently of its antidepressant effects. Both formulations of the drug are effective when used as monotherapy or adjunctively with antidepressants or mood stabilizers. Beyond symptom control, both formulations improved patient functioning and increased patient satisfaction.     

Microemulsions for oral administration and their therapeutic applications

Introduction: The microemulsion concept was introduced in 1943 by Hoar and Schulman. Self-microemulsifying drug delivery systems (S(M)EDDS) are much more recent and can be described as isotropic solutions of oils and surfactants that form oil-in-water O/W microemulsions when they are poured into an aqueous medium. When they are presented as soft capsules for oral delivery, S(M)EDDS have the ability to considerably improve the intestinal absorption of agents that are incorporated into the S(M)EDDS. Forty percent of newly discovered drug candidates have little or no water solubility and therefore have low and/or variable bioavailability profiles. Many of these drugs are good candidates for formulation into S(M)EDDS.

Areas covered: This paper describes the preparation and assessment of these formulations and their current applications. The characterisation of this type of formulation has improved, and in vitro models (Caco-2 cell cultures, Ussing chambers, the everted sac technique, etc.) can be used for screening different formulations. It describes also marketed formulations (i.e., cyclosporin and saquinavir S(M)EDDS) and some other formulations.

Expert opinion: Actual applications of S(M)EDDS remain rare. The first drug marketed as a S(M)EDDS was cyclosporin, and it had significantly improved bioavailability compared with the conventional solution. In the last decade, several S(M)EDDS loaded with antiviral drugs (e.g., ritonavir, saquinavir) were tested for treatment of HIV infection, but the relative improvement in clinical benefit was not significant. The S(M)EDDS formulation of Norvir® (soft capsules) has been withdrawn in some countries.     

Vaginal gel drug delivery systems: understanding rheological characteristics and performance

Introduction: Vaginal gels are used for a wide range of clinical and pharmaceutical applications. Gel performance in vivo, including spreading ability, retention and drug release behavior, is closely related to rheological properties. Hence, a comprehensive rheological characterization of candidate gel formulations is important in screening and designing appropriate vaginal gels to achieve optimal clinical performance.

Areas covered: In this review, the basic destructive (flow) and non-destructive (oscillation and creep) techniques, commonly used in the assessment of gels, are introduced. The main rheological properties discussed in this work include viscosity, storage modulus, loss modulus, loss tangent and strain growth under small stress loads. In particular, this paper reviews the rheological methods used in characterizing vaginal gels and discusses the factors that may influence rheological performance. Recent advances in rheological methods, the use of advanced rheological methods and the challenges facing formulation scientists are also reviewed.

Expert opinion: The complex and dynamic environment of the vagina requires a comprehensive understanding of the rheological performance of vaginal gels. The establishment of suitable rheological tests to appropriately define such characteristics may facilitate the selection of a gel that avoids leakage. The ideal gel platform must provide adequate coating with minimal leakage. This is extremely difficult to obtain as it requires the formulation of a gel with a suitable viscoelastic balance.     

Physico-Chemical Properties,Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Purpose

Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution.

Methods

The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated.

Results

The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5?±?4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations.

Conclusions

We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.