Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital^? inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200?mg of 50:50?w/w AZ: mannitol had 57.6%?±?7.6% delivery efficiency with a fine particle fraction (≤6.8?µm) of the emitted aerosol cloud being 80.4%?±?1.1%, with minimal throat deposition (5.3?±?0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.     

Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb)

Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting.     

Dry powder nasal drug delivery: challenges,opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation

Purpose: To discuss the challenges and opportunities for dry powder nasal medications and to put this in to perspective by evaluating and characterizing the performance of the Teijin beclomethasone dipropionate (BDP) dry powder nasal inhaler; providing a baseline for future nasal products development.

Methods: The aerosol properties of the formulation and product performance of Teijin powder intranasal spray were assessed, with a particular focus on particle size distribution (laser diffraction), powder formulation composition (confocal Raman microscope) and aerosol performance data (British Pharmacopeia Apparatus E cascade impactor, aerosol laser diffraction).

Results: Teijin Rhinocort^® (BDP) dry powder spray formulation is a simple blend of one active ingredient, BDP with hydroxypropylcellulose (HPC) carrier particles and a smaller quantity of lubricants (stearic acid and magnesium stearate). The properties of the blend are mainly those of the carrier (D_v50?=_?98?±?1.3?µm). Almost the totality of the capsule fill weight (96.5%) was emitted with eight actuations of the device. Using the pharmacopeia suggested nasal chamber deposition apparatus attached to an Apparatus E impactor. The BDP main site of deposition was found to be in the nasal expansion chamber (90.2?±?4.78%), while 4.64?±?1.38% of the BDP emitted dose was deposited on Stage 1 of the Apparatus E.

Conclusions: The Teijin powder nasal device is a simple and robust device to deliver pharmaceutical powder to the nasal cavity, thus highlighting the robustness of intranasal powder delivery systems. The large number of actuations needed to deliver the total dose (eight) should be taken in consideration when compared to aqueous sprays (usually two actuations), since this will impact on patient compliance and consequently therapeutic efficacy of the formulation.     

Micronized drug powders in binary mixtures and the effect of physical properties on aerosolization from combination drug dry powder inhalers

Objectives: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. Methods: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. Results: The median SS particle diameter was larger than BDP (4.33?±?0.37 µm compared to 2.99?±?0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. Conclusions: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.     

Inhaled PYY(3–36) dry-powder formulation for appetite suppression

Objective: Peptide YY3–36 [PYY(3–36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3–36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study.

Methods: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3–36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3–36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data.

Results: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2?×?higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65?mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4?h, which is similar to IP and subcutaneous delivery routes.

Conclusions: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3–36). Additionally, engineered PYY(3–36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression.     

In vitro and in vivo evaluations of a novel pulsed and controlled osmotic pump capsule

Objective: For better treatment of circadian cardiovascular events, a novel Propranolol hydrochloride (PNH) delayed-release osmotic pump capsule was developed.

Methods: The capsule body was designed of asymmetric membrane and the capsule cap was made impermeable. The physical characteristics of capsule body walls and membrane permeability were compared among different coating solutions.

Results: The formulation with the glycerin and diethyl phthalate (DEP) ratio of 5:4 appeared to be the best. The lag time and subsequent drug release were investigated through assembling the capsule body with capsule caps of different length. WSR N-10 was chosen as the suspending for its moderate expanding capacity. The influence of factors (WSR N-10 content, NaCl content and capsule cap length) on the responses (lag time and drug release rate) was evaluated using central composite design-response surface methodology. A second-order polynomial equation was fitted to the data and actual response values were in good accordance with the predicted ones. The optimized formulation displayed complete drug delivery, zero-order release rate with 4-h lag time. The results of in vivo pharmacokinetics in beagle dogs clearly suggested the controlled and sustained release of PNH from the system and that the relative bioavailability of this preparation was about 1.023 comparing the marketed preparation.

Conclusions: These results indicate that by the adjustment of capsule cap length, PNH could be developed as a novel pulsatile and controlled drug delivery system.     

Preparation and evaluation of poly(lactic-co-glycolic acid) microparticles as a carrier for pulmonary delivery of recombinant human interleukin-2: II. In vitro studies on aerodynamic properties of dry powder inhaler formulations

Objective: The aim of this study was the preparation and evaluation of dry powder formulations of recombinant human interleukin-2 (rhIL-2)-loaded microparticles to be administered to the lung by inhalation.

Methods: As indicated in our previous study, the microparticles were prepared by modified water-in-oil-in-water (w₁/o/w₃) double emulsion solvent extraction method using poly(lactic-co-glycolic acid) (PLGA) polymers. The dry powder formulations were prepared with blending of microparticles and mannitol as a coarse carrier. The actual aerodynamic characteristics of the microparticles alone and prepared mixtures with mannitol are evaluated by using the eight-stage Andersen cascade impactor.

Results: Due to the low tapped density of microparticles (<0.4?g/cm³), the theoretical aerodynamic diameter (MMADt) values were calculated (<5 μm) on the basis of the geometrical particle diameter and tapped density values. The lowest tapped density value (0.17?g/cm³) belongs to the cyclodextrin-containing formulation. According to the results obtained using the cascade impactor, the emitted doses for all microparticle formulations were found to be rather high and during the aerosolization for all the formulations except F3 and F5, >90% of the capsule content was determined to be released. However, the actual aerodynamic diameter (MMADa) values were seen to be higher than the MMADt values. The blending of the microparticles with mannitol allowed their aerodynamic diameters to decrease and their fine particle fraction values to increase.

Conclusion: The obtained results have shown that the mixing of rhIL-2-loaded microparticles with mannitol possess suitable aerodynamic characteristics to be administered to the lungs by inhalation.     

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation

Abstract

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na₂CO₃ at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12?h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.     

Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution

Abstract

Context: Gabapentin was selected to formulate oral controlled release dry suspension because of short biological half life of 5–7?h and low bioavailability (60%). Gabapentin is a bitter drug so an attempt was made to mask its taste.

Objective: To formulate and evaluate controlled release dry suspension for reconstitution to increase the bioavailability and to control bitter taste of drug.

Materials and methods: Cyclodextrin based nanosponges were synthesized by previously reported melt method. The nanosponge–drug complexes were characterized by FTIR, DSC and PXRD as well as evaluated for taste and saturation solubility. The complexes were coated on Espheres by a suspension layering technique followed by coating with ethyl cellulose and Eudragit RS-100. A dry powder suspension for reconstitution of the microspheres was formulated and evaluated for taste, redispersibility, in vitro dissolution, sedimentation volume, leaching and pharmacokinetics.

Results and discussion: The complexes showed partial entrapment of drug nanocavities. Significant decrease in solubility (25%) was observed in the complexes than pure drug in different media. The microspheres of nanosponge complexes showed desired controlled release profile for 12?h. Insignificant drug leaching was observed in reconstituted suspension during storage for 7 days at 45?°C/75% RH. Nanosponges effectively masked the taste of Gabapentin and the coating polymers provided controlled release of the drug and enhanced taste masking. The results of in vivo studies showed increase in bioavailability of controlled release suspension by 24.09% as compared to pure drug.

Conclusion: The dry powder suspension loaded with microspheres of nanosponges complexes can be proposed as a suitable controlled release drug delivery for Gabapentin.     

In vivo absorption comparison of nanotechnology-based silybin tablets with its water-soluble derivative

In this study, the in vivo oral absorption of a nanocrystal tablet formulation of a BCS II poorly water-soluble drug was compared with that of its water-soluble salt form. Silybin is used as the model drug, and its nanosuspension was prepared by high-pressure homogenization. Effect of process and formulation parameters on properties of the nansuspensions was investigated. Dried powder of the nanosuspension was prepared by spray drying and used for preparing tablets. A pharmacokinetic study was performed in Beagle dogs to compare the absorption for tablets of silybin nanocrystals and silybin meglumine. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was determined. X-ray powder diffraction results indicated that silybin existed in a crystalline state after homogenization. In vivo absorption study in rats showed that the peroral absorption of silybin was enhanced remarkably by decreasing particle size. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was comparable with that of the commercially available tablet of the water-soluble salt form of silybin. In conclusion, it is possible to increase the bioavailability of poorly soluble drugs by preparing its water-soluble derivative.     

In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization

Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.

Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.

Results and discussion: There was a big deviation between the T_g of the polymeric caplet from the T_g's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.

Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

A New Apparatus for the Determination of the Emitted Dose from Pressurized Metered Dose Inhalation Aerosols with Inhalation Devices

Abstract

A new in vitro test apparatus is described in this report to test the emitted dose from the pressurized metered dose inhalation aerosols (MDI) with inhalation devices. Drug deposition from MDIs in conjunction with different inhalation chambers was studied using a new apparatus and compendial apparatuses. The new apparatus is simple and offers an alternate method to determine the small particle fraction delivered from MDI aerosols with inhalation devices.     

E-SPART Analysis of Poly (D,L-lactide-co-glycolide) Microspheres Formulated for Dry Powder Aerosols

ABSTRACT

Electrical-single particle aerodynamic relaxation time (E-SPART) analysis was studied as a tool in formulation screening of diy powders for use in aerosol delivery to the lung. The respirable fraction (RF) of drugs delivered by dry powder inhalers (DPIs) can be improved more effectively by using hydrophobic microspheres as carriers. Poly (D,L-lacttde-co-grycolide) microspheres (PLGA) prepared in die respirable size range (3-7 mm) were treated with poryamino acids and isopropanol in order to obtain particles of surface charge suitable for use in DPIs.

The powder formulations were evaluated for their degree of aggregation by cascade impaction following delivery by the Pfeifler® DPI. The IPA treated PLGA microspheres had a significantly higher RF (12.9%) as compared to the PL and PGA treated microspheres (3.3 and 2.4%, respectively), and untreated microspheres (3.8%). Results of electrostatic charge determined by E-SPART analysis suggested that die higher RF for the IPA formulation may be due to hs highly unipolar nature (+ 56.3 mC/g).     

Inhalable liposomes of Glycyrrhiza glabra extract for use in tuberculosis: formulation,in vitro characterization,in vivo lung deposition,and in vivo pharmacodynamic studies

Objective: The current study involves the development of liposomal dry powder for inhalation (LDPI) containing licorice extract (LE) for use in tuberculosis.

Significance: The current epidemiology of tuberculosis along with the increasing emergence of resistant forms of tuberculosis necessitates the need for developing alternative efficacious medicines for treatment. Licorice is a medicinal herb with reported activity against Mycobacterium tuberculosis.

Methods: Liposomes with LE were prepared by thin film hydration technique and freeze dried to obtain LDPI. The comprehensive in vitro and in vivo characterization of the LDPI formulation was carried out.

Results: The particle size of liposomes was around 210?nm with drug entrapment of almost 75%. Transmission electron microscopy revealed spherical shape of liposome vesicles. The flow properties of the LDPI were within acceptable limits. Anderson Cascade Impactor studies showed the mean median aerodynamic diameter, geometric standard deviation and fine particle fraction of the LDPI to be 4.29?µm, 1.23, and 54.68%, respectively. In vivo lung deposition studies of LDPI in mice showed that almost 46% of the drug administered reaches the lungs and 16% of administered drug is retained in the lungs after 24?hours of administration. The in vivo pharmacodynamic evaluation of the LDPI showed significant reduction in bacterial counts in lungs as well as spleen of TB-infected mice.

Conclusions: LE LDPI thus has a promising potential to be explored as an effective anti-tubercular medicine or as an adjunct to existing anti-tubercular drugs.     

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery

Objective: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus^® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route.

Significance: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray.

Methods: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus–BUD formulation.

Results: The freeze-dried Soluplus–BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334?±?0.0178 m²/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension.

Conclusions: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.     

PARTICLES AS DRUG DELIVERY SYSTEMS

ABSTRACT

Advances in genetically engineered products present an entirely new spectrum of drugs to the medical community. With these exciting new drugs come complex challenges for their delivery. The compounds are often high molecular weight proteins, many with extremely short in vivo half lives. The challenge is to deliver these new drugs to the body at a controlled rate. The rate can be uniform or programmed to a specific regimen, with time frames from hours to months. An additional challenge is posed by drugs that are highly toxic. If the drug were to home in directly on the site of action, systemic damage could be minimized. Drug loaded particles, (emulsions, liposomes or microcapsules), are being developed for both controlled and targeted drug delivery.     

Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development,physico-chemical characterization and in vitro evaluation

Context: This study presents novel nanostructured oil-in-water (o/w) mists based on self-nanoemulsifying (SNE) mixtures capable of delivering poorly water-soluble drugs into the lungs.

Objective: Formulation development of an o/w nanoemulsion (NE) capable of being nebulized for pulmonary delivery of poorly water-soluble drugs.

Materials and methods: SNE mixtures were prepared and evaluated using Tween 80 and Cremophor RH 40 as surfactants; Transcutol P, Capryol 90 and PEG 400 as cosurfactants; and Labrafac Lipophile Wl 1349 (a medium-chain triglyceride) as an oil. Liquid NEs were analyzed by light scattering, zeta potential, transmission electron microscopy (TEM) and in vitro drug release studies. The aqueous NE was nebulized and assessed by light scattering and TEM. The formulation was aseptically filtered and the sterility validated. In vitro cytotoxicity of the formulations was tested in NIH 3T3 cells. The capability of the formulation to deliver a poorly water-soluble drug was determined using ibuprofen.

Results: Ibuprofen was found to be stable in the NEs. The formulations were neutrally charged with a droplet size of about 20?nm. TEM images displayed 100?nm oil droplets. The aseptic filtration method produced sterile NE. The nebulized mist revealed properties ideal for pulmonary delivery. The biocompatible aerosol has a nanostructure consisting of several oil nanodroplets enclosed within each water drop. Solubility and in vitro drug release studies showed successful incorporation and release of ibuprofen.

Conclusion: The developed formulation could be used as an inhalation for delivering material possessing poor water solubility into the lungs.     

Engineering of poly(DL-lactic-co-glycolic acid) nanocomposite particles for dry powder inhalation dosage forms of insulin with the spray-fluidized bed granulating system

The objective of the present research is to develop a new particulate preparation process for dry powder inhalation by which peptide-loaded poly(DL-lactic-co-glycolic acid) nanospheres are granulated with sugar alcohol (mannitol, around 4 μm in diameter). A spray-drying fluidized bed granulator was used to form soft matrix composite granules. A nanosphere suspension can be readily obtained by dispersing the composite granules in distilled water. The composite granules showed inhalation performance superior to that of freeze-dried nanosphere powder. More than 50% of composite granules were delivered to the bronchioles and alveoli of a rat. The composite granules of insulin-loaded nanosphere have a strong and prolonged pharmacological effect compared to the inhalation of insulin solution.