Targeted Respiratory Tract Drug Delivery Systems
Roxane Abdel Gawad Moussa;
Abstract
Direct drug targeting to its site of action offers always numerous advantages over traditional routes. Targeting drugs to lungs was recently considered as a promising route of administration of drugs for both local action in lungs or to the systemic circulation.
The pulmonary route offers large surface area for drug absorption, with little or no enzymatic activity. Thus avoidance the first pass effect presented lungs as an alternative to the systemic route for administration of proteins, hormones and other macromolecules with high systemic bioavailability. For drug exerting their action in lungs for treatment of asthma, fibrosis or lungs infections, targeting allows the use of smaller drug doses with little or no systemic side effects.
Dry powder platform is delivered to the lungs using dry powder inhalers, offering long term stability being in a dry state. The powder should have suitable mass median aerodynamic diameter to allow for deep deposition in alveoli, where high surface area and thin non ciliated wall offering no barriers for the deposited particles. It is to be noted that the freely roaming macrophages in alveoli can engulf and digest the deposited particles. So, after deposition, fast dissolution of particles (if soluble) or fast deaggregation to their payload of nanoparticles is a crucial step to skip these macrophages, unless macrophage targeting was an aim.
Montelukast (MTK) is a novel antiasthma drug of the leukotriene inhibitor group. It has been used for the management of asthma specially in children, when avoidance of corticosteroids therapy is a must. The aim of this work was to develop MTK dry powder formulations for both fast and prolonged drug action.
Accordingly, the work was divided to three chapters as follows:
• Chapter I: Preparation and Characterization of Fast Dissolving MTK Loaded Spray Dried Agglomerated Microparticles.
• Chapter II: Preparation and Characterization of Agglomerated Spray Dried MTK Loaded PLGA Nano-In-Microparticles.
• Chapter III: In-Vivo Pharmacologic Efficacy of MTK loaded Spray Dried Powders Formulae.
Chapter I: Preparation and Characterization of Fast Dissolving MTK Loaded Spray Dried Agglomerated Microparticles.
This chapter was concerned with the preparation of agglomerated fast dissolving MTK loaded microparticles using the spray drying technique. Two types of matrix formers were studied in this chapter, mannitol and ovalbumin. For each type of soft agglomerates, varying ratios of different excipients and drug were prepared and characterized viz: powder yield, drug content, flow parameters, particle size, aerosolization properties, particle size analysis. X ray powder diffraction, Differential scanning calorimetry, Fourier transform infrared spectroscopy were used also to evaluate the prepared powder formulae. The developed agglomerates were visualized using scanning electron microscopy, deagglomeration study was also performed to evaluate the ability of the soft agglomerates to deagglomerate under reduced pressures. Finally, in-vitro release study and long term stability study were performed on the selected formula.
The results of this chapter could be summarized in the following points:
1. Non polymer based MTK loaded agglomerated microparticles were successfully prepared with the spray drying technique using mannitol and ovalbumin as matrix formers.
2. Spray drying of drug with mannitol alone or in combination with leucine showed an acceptable powder yield. The spray dried drug alone or in combination with high albumin content showed very low yields and sticking of the dried powder to the cyclone wall. This indicated the need of suitable excipients in order to formulate MTK in a stable dry powder platform with acceptable properties.
3. The association efficiency of all formulae was more than 90%, indicating the suitability of the method of preparation and spray drying conditions, allowing for no drug loss.
4. Leucine proved to be an essential additive for producing powder with acceptable flow properties. Increasing its percent in the final formulae yielded powders with good aerosolization properties and high fine particle fraction.
5. X Ray diffractogram showed that the drug was successfully amorphized after spray drying, allowing for rapid drug dissolution after deposition. Residual excipients crystallinity was also evident with both mannitol and leucine, offering more chemical and physical stability than the completely amorphous powders. This residual crystallinity was not detected in ovalbumin as additive, and the residual crystallinity in ovalbumin based formulae was originated from leucine only.
6. Agglomeration was successfully achieved using 5% lecithin as soft binder. This agglomeration was confirmed by particle size measurements and SEM imaging of both types of agglomerates. The agglomerates showed rough surface with mannitol, in albumin based formulae, corrugated surface was obtained.
7. The mass median aerodynamic diameter of all formulae lied between 1 and 5 µm, indicating the successful production of inhalable powders suitable for pulmonary delivery.
8. The produced agglomerates were soft enough to restore their original size by applying different air pressures during dry particle size measurement.
9. The produced microparticles were fast dissolving, as proved in the in-vitro release study. Where more than 95% of MTK was released from the tested soft agglomerates within the first 5 minutes. Allowing to skip uptake by the freely roaming macrophages in alveoli, as this engulfment starts within 30 minutes after particles deposition.
10. The use of twin stage impinger proved the production of inhalable powders with expected suitable deposition in the deep alveoli when administered via the pulmonary route. Formulae containing 50% leucine (namely M4 and O4) showed best fine particle fraction and aerosolization properties.
11. Mannitol based soft agglomerates offered drug loading flexibility as evidenced in the in-vitro pulmonary deposition. Where increasing drug loading was found to have no negative impact on the aerosolization properties of the prepared powders. On the contrary, for albumin based soft agglomerates, high drug loading adversely affected powder deposition.
12. The selected formula (M4) showed long term stability for up to six months at normal storage conditions. This might be attributed to both, its low residual moisture content, and the residual excipients crystallinity which protected the drug payload from any degradation upon storage.
13. The successfully agglomerated formula M4 (D5:M40:L50: S5), with best yield value (87.23), best powder flow properties, highest stage 2 deposition and fastest dissolution profile, drug loading flexibility and low residual moisture content, was selected for further in-vivo characterization.
The pulmonary route offers large surface area for drug absorption, with little or no enzymatic activity. Thus avoidance the first pass effect presented lungs as an alternative to the systemic route for administration of proteins, hormones and other macromolecules with high systemic bioavailability. For drug exerting their action in lungs for treatment of asthma, fibrosis or lungs infections, targeting allows the use of smaller drug doses with little or no systemic side effects.
Dry powder platform is delivered to the lungs using dry powder inhalers, offering long term stability being in a dry state. The powder should have suitable mass median aerodynamic diameter to allow for deep deposition in alveoli, where high surface area and thin non ciliated wall offering no barriers for the deposited particles. It is to be noted that the freely roaming macrophages in alveoli can engulf and digest the deposited particles. So, after deposition, fast dissolution of particles (if soluble) or fast deaggregation to their payload of nanoparticles is a crucial step to skip these macrophages, unless macrophage targeting was an aim.
Montelukast (MTK) is a novel antiasthma drug of the leukotriene inhibitor group. It has been used for the management of asthma specially in children, when avoidance of corticosteroids therapy is a must. The aim of this work was to develop MTK dry powder formulations for both fast and prolonged drug action.
Accordingly, the work was divided to three chapters as follows:
• Chapter I: Preparation and Characterization of Fast Dissolving MTK Loaded Spray Dried Agglomerated Microparticles.
• Chapter II: Preparation and Characterization of Agglomerated Spray Dried MTK Loaded PLGA Nano-In-Microparticles.
• Chapter III: In-Vivo Pharmacologic Efficacy of MTK loaded Spray Dried Powders Formulae.
Chapter I: Preparation and Characterization of Fast Dissolving MTK Loaded Spray Dried Agglomerated Microparticles.
This chapter was concerned with the preparation of agglomerated fast dissolving MTK loaded microparticles using the spray drying technique. Two types of matrix formers were studied in this chapter, mannitol and ovalbumin. For each type of soft agglomerates, varying ratios of different excipients and drug were prepared and characterized viz: powder yield, drug content, flow parameters, particle size, aerosolization properties, particle size analysis. X ray powder diffraction, Differential scanning calorimetry, Fourier transform infrared spectroscopy were used also to evaluate the prepared powder formulae. The developed agglomerates were visualized using scanning electron microscopy, deagglomeration study was also performed to evaluate the ability of the soft agglomerates to deagglomerate under reduced pressures. Finally, in-vitro release study and long term stability study were performed on the selected formula.
The results of this chapter could be summarized in the following points:
1. Non polymer based MTK loaded agglomerated microparticles were successfully prepared with the spray drying technique using mannitol and ovalbumin as matrix formers.
2. Spray drying of drug with mannitol alone or in combination with leucine showed an acceptable powder yield. The spray dried drug alone or in combination with high albumin content showed very low yields and sticking of the dried powder to the cyclone wall. This indicated the need of suitable excipients in order to formulate MTK in a stable dry powder platform with acceptable properties.
3. The association efficiency of all formulae was more than 90%, indicating the suitability of the method of preparation and spray drying conditions, allowing for no drug loss.
4. Leucine proved to be an essential additive for producing powder with acceptable flow properties. Increasing its percent in the final formulae yielded powders with good aerosolization properties and high fine particle fraction.
5. X Ray diffractogram showed that the drug was successfully amorphized after spray drying, allowing for rapid drug dissolution after deposition. Residual excipients crystallinity was also evident with both mannitol and leucine, offering more chemical and physical stability than the completely amorphous powders. This residual crystallinity was not detected in ovalbumin as additive, and the residual crystallinity in ovalbumin based formulae was originated from leucine only.
6. Agglomeration was successfully achieved using 5% lecithin as soft binder. This agglomeration was confirmed by particle size measurements and SEM imaging of both types of agglomerates. The agglomerates showed rough surface with mannitol, in albumin based formulae, corrugated surface was obtained.
7. The mass median aerodynamic diameter of all formulae lied between 1 and 5 µm, indicating the successful production of inhalable powders suitable for pulmonary delivery.
8. The produced agglomerates were soft enough to restore their original size by applying different air pressures during dry particle size measurement.
9. The produced microparticles were fast dissolving, as proved in the in-vitro release study. Where more than 95% of MTK was released from the tested soft agglomerates within the first 5 minutes. Allowing to skip uptake by the freely roaming macrophages in alveoli, as this engulfment starts within 30 minutes after particles deposition.
10. The use of twin stage impinger proved the production of inhalable powders with expected suitable deposition in the deep alveoli when administered via the pulmonary route. Formulae containing 50% leucine (namely M4 and O4) showed best fine particle fraction and aerosolization properties.
11. Mannitol based soft agglomerates offered drug loading flexibility as evidenced in the in-vitro pulmonary deposition. Where increasing drug loading was found to have no negative impact on the aerosolization properties of the prepared powders. On the contrary, for albumin based soft agglomerates, high drug loading adversely affected powder deposition.
12. The selected formula (M4) showed long term stability for up to six months at normal storage conditions. This might be attributed to both, its low residual moisture content, and the residual excipients crystallinity which protected the drug payload from any degradation upon storage.
13. The successfully agglomerated formula M4 (D5:M40:L50: S5), with best yield value (87.23), best powder flow properties, highest stage 2 deposition and fastest dissolution profile, drug loading flexibility and low residual moisture content, was selected for further in-vivo characterization.
Other data
| Title | Targeted Respiratory Tract Drug Delivery Systems | Other Titles | أنظمة إيتاء دوائية رئوية مهدفه | Authors | Roxane Abdel Gawad Moussa | Issue Date | 2016 |
Attached Files
| File | Size | Format | |
|---|---|---|---|
| G10809.pdf | 404.44 kB | Adobe PDF | View/Open |
Similar Items from Core Recommender Database
Items in Ain Shams Scholar are protected by copyright, with all rights reserved, unless otherwise indicated.