Evaluation Study of Nasal Drug Delivery System Using Spray Drying Technique

D. S. Wanjari¹*, Dr M.D. Kshirsagar²

¹*Research Scholar, P. Wadhawani College of Pharmacy, Yeotmal,

²Professor, P. Wadhawani College of Pharmacy, Yeotmal,

*Corresponding Author E-mail: wanjarids@rediffmail.com

ABSTRACT:

In the present research work it has been studied the various evaluation parameters for the nasal drug delivery system using spray drying technique. The bulk density was mainly influenced by the solid fraction of the dispersion prepared prior to freeze-drying. The bulk density of the powder formulations had no influence on the nasal bioavailability of insulin in rabbits. From this study, it was concluded that the procedure for preparation of the nasal powder formulations was a robust production method. In the present study it has been demonstrated that the selection of an appropriate delivery system is a critical issue in the development of nasal powder formulations.

KEYWORDS: Nasal powder formulations, bulk density, freeze-drying, spray drying technique.

INTRODUCTION:

Nasally administered drugs (especially in the case of peptides and proteins) encounter several barriers before reaching the systemic circulation. These barriers include the mucus and epithelium (a physical barrier), the mucociliary clearance (a temporal barrier) and the enzymatic activity (a chemical barrier), resulting in a low bioavailability of peptides and proteins. To achieve sufficient absorption via the nasal route, simultaneous administration of peptides, absorption enhancers and/or enzyme inhibitors has been extensively investigated. Another approach to increase the nasal bioavailability has been to prolong the residence time of the formulation in the nasal cavity.

This research project will focus on powder formulations as carriers for the nasal delivery of peptides, aiming to improve the nasal bioavailability of the drug by enhancing the residence time of the drug in the nasal cavity due to the incorporation of viscosity-enhancing excipients in the formulation. Nasal powder formulations are preferred to liquid formulations as the chemical stability of the drug is increased. as the small volume of the nasal cavity limits the amount that can be administered, it is only suitable for the administration of low-dose or high solubility drugs via a simple liquid formulation. In contrast, powder formulations allow administering a larger amount of drug and excipients, increasing the residence time of the drug in the nasal cavity and possibly saturating the enzymatic degradation processes due the high drug concentrations obtained at the nasal mucosa. Furthermore, no preservatives are required in dry powder formulations.

MATERIAL AND METHOD:

Insulin was a gift sample from Ciron Drugs Ltd., Drum Dried Waxy Maize starch and poly(acrylic acid) (Carbopol®) 974P, Spray-dried Amioca® starch, Calcitonin was a gift sample from Loba Chemie, Mumbai. All other chemicals were of analytical grade.

Formulation Development:

Insulin formulations:

Insulin solution for intravenous administration:

An insulin solution of 0.8 IU/ml was prepared by diluting Actrapid^® HM 100 in a phosphate buffered saline solution (PBS, pH 7.4) (2.38 g Na2HPO4.2H2O, 0.19 g KH2PO4 and 8.0 g NaCl per liter distilled water) of which 0.5 ml was administered intravenously to rabbits (n = 10).

Nasal powder formulations:

Dispersions containing a physical mixture of DDWM and C 974P (ratio: 95/5, w/w) (DDWM/C 974P 95/5) were prepared in a concentration of 2.0, 5.0 and 8.5 % (w/w), whereas dispersions containing a spray-dried mixture of Amioca^® starch and C 974P (ratio: 25/75, w/w) (SD 25/75) were prepared in a concentration of 1.0, 2.5 and 7.0 % (w/w). To prepare the dispersions containing 2.0 and 5.0 % DDWM/C 974P 95/5, 1.0 g powder was dispersed in 10.0 ml distilled water and to prepare the dispersions containing 1.0 and 2.5 % SD 25/75, 1.0 g powder was dispersed in 30.0 ml distilled water. To prepare the dispersions containing 8.5 % DDWM/C 974P 95/5 and 7.0 % SD 25/75, 1.0 g powder was hydrated with 1.0 and 2.0 ml distilled water, respectively. After neutralisation of the dispersions containing DDWM/C 974P 95/5 and SD 25/75 to pH 7.4 with 0.2 M and 2.0 M NaOH, respectively, the insulin solution (Actrapid® HM 100) was added to obtain a final concentration of 1 IU insulin per mg powder. Finally distilled water was added until the desired concentration was obtained. The selection of the solid fractions of the dispersions was based on the consistency of the dispersions: dispersions having the lowest solid fraction had a liquid-like structure, dispersions with the intermediate solid fraction had a gel-like structure and dispersions with the highest solid fraction was the highest which could be prepared. The dispersions were Spray-dried in vials using an Amsco-Finn Aqua GT4 Spray -dryer (Amsco, Germany). The dispersions were frozen to 228 K within 175 min at 1000 mbar. Additionally, the dispersions containing 5.0 % DDWM/C 974P 95/5 and 2.5 % SD 25/75 were frozen to 228 K within 30 min and 350 min. Primary drying was performed at 258 K and at a pressure varying between 0.8 and 1 mbar during 13 h, followed by secondary drying at elevated temperature (283 K) and reduced pressure (0.1 - 0.2 mbar) for 7 h. After Spray drying the powder was sieved (63 μm) at low relative humidity (20 %) and ambient temperature. The fraction below 63 μm was stored in a desiccator at 4 - 8 °C until use.

Evaluation:

Nasal bioavailability:

White rabbits (3.0 ± 0.5 kg) were fasted 16 h prior to the experiment. Water was available ad libitum. They were sedated with an intramuscular injection of 0.05 ml/kg. The rabbits received 0.4 IU insulin intravenously. The powder was administered intranasally using polyethylene tubes filled with 5.0 mg of the DDWM/C 974P 95/5 powder formulation or 10.0 mg of the SD 25/75 powder formulation. 10 mg powder (equivalent to 10 IU insulin) was administered in each nostril. In case of DDWM/C 974P 95/5 2 tubes filled with 5.0 mg powder were delivered into each nostril. The delivery device was filled under conditions of low relative humidity (20 %) and ambient temperature. Blood samples were collected from the ear veins at -5, 1, 5, 10, 15, 20, 30, 40, 50 and 60 min after intravenous administration and at -5, 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90, 120, 150 and 180 min after nasal delivery of the powders. The samples were centrifuged (700g, 5 min) and the sera were frozen at –20 °C.

Determination of Bulk Density:

The apparent powder bulk density (defined as the ratio of the powder weight over its bulk volume) was determined in the polyethylene tubes of the nasal delivery device filled with 5.0 mg of the Spray-dried DDWM/C 974P 95/5 mixture or 10.0 mg of the Spray-dried SD 25/75 mixture. Results are presented as a mean value ± standard deviation (n = 10).

Determination of Particle Size:

The particle size of the powder formulations was determined by laser diffraction, using Miglyol 812N (caprylic/capric acid triglycerides) as dispersion medium. The volume median diameter (VMD) was calculated.

Moisture Content:

The moisture content was determined using a Mettler DL 35 Karl Fischer titrator. Hydranal-Composite 2 was used as titrant and anhydrous methanol as reaction medium. Calibration and verification of the titrant (theoretical 2 mg H2O/ml) was performed with distilled water. Results are presented as a mean value ± standard deviation (n = 3).

RESULTS AND DISCUSSION:

Nasal Bioavailability:

Table 1. Absolute bioavailability, Cmax and tmax (mean ± SD) after nasal delivery to rabbits of powder formulations (1 IU insulin/mg) obtained by Spray-drying Formulation containing 5.0 % DDWM/C 974P 95/5 or 2.5 % SD 25/75 at different drying rates.

Spray-Dried	BA (%)	Cmax (μIU/ml)	Tmax (min)	n
DDWM/C 974P 95/5
30 min	5.4 ± 2.6	281.1 ± 192.8	29.9 ± 5.3	7
175 min	9.2 ± 3.0	497.1 ± 184.6	23.3 ± 5.5	8
350 min	8.2 ± 3.0	478.7 ± 163.0	22.4 ± 4.4	8
SD 25/75
30 min	18.2 ± 3.7	708.4 ± 210.2	41.5 ± 9.3	7
175 min	19.2 ± 5.3	681.4 ± 246.6	50.9 ± 7.4	8
350 min	22.4 ± 3.3	852.4 ± 84.0	40.9 ± 11.7	6

Spray drying	Bulk density (mg/μl)	VMD (μm)	Residual moisture (%)

DDWM/C 974P 95/5
30 min	0.060 ± 0.004	71.2	6.41 ± 0.21
175 min	0.058 ± 0.004	62.1	5.04 ± 0.12
350 min	0.063 ± 0.006	47.7	4.72 ± 0.15
SD 25/75
30 min	0.202 ± 0.010	61.3	3.55 ± 0.24
175 min	0.165 ± 0.016^a	51.9	7.54 ± 0.99
350 min	0.160 ± 0.014 ^a	48.5	3.72 ± 0.22

CONCLUSION:

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Received on 21.07.2016 Accepted on 28.09.2016

Research J. Topical and Cosmetic Sci. 2016; 7(2): 67-69.

DOI: 10.5958/2321-5844.2016.00010.8