Buccal drug delivery system

Among the various routes of drug delivery, the peroral has been one of the most convenient and widely accepted routes of delivery for most therapeutic agents. However, peroral administration of drugs has disadvantages, such as hepatic first-pass metabolism and enzymatic degradation within the gastrointestinal tract. These disadvantages may limit or prevent the oral administration of certain classes of drugs, especially peptides and proteins. Transmucosal routes of drug delivery offer distinct advantages over peroral administration for systemic drug delivery. These advantages include possible bypass of first-pass effect and avoidance of presystemic elimination within the gastrointestinal tract (Bruschi et al., 2005). The mucosal layer lines a number of regions of the gastrointestinal tract, the airways, the ear, nose, and the eye, and hence, the mucoadhesive drug delivery system includes the following.

• Buccal delivery system
• Sublingual delivery system
• Vaginal delivery system
• Rectal delivery system
• Nasal delivery system
• Ocular delivery system

Factors affecting mucoadhesion4-6

Polymer-related factors

• Molecular weight

  The bioadhesive strength of a polymer increases with molecular weights above 1,00,000. The fact that bioadhesiveness improves with increasing molecular weight for a linear polymer implies two things: (1) Interpenetration is more critical for low molecular weight polymer to be a good bioadhesive and (2) entanglement is important for high molecular weight polymers.

• Concentration of active polymer

  When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable.

• Flexibility of polymer chains

  Chain flexibility is critical for interpenetration and entanglement. As water soluble-polymers become cross-linked, mobility of an individual polymer chain decreases and thus the effective length of the chain that can penetrate into the mucus layer decreases which reduces bioadhesive strength.

• Charge

  Nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers. Some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium.

• Cross-linking density

  The average pore size, the number average molecular weight of the cross-linked polymers, and the density of cross-linking are three important and interrelated structural parameters of a polymer network.

• Swelling

  Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network.

Environment-related factors

• pH of polymer-substrate interface

  pH can influence the formal charge on the surface of the mucus as well as certain ionizable bioadhesive polymers.

Physiological factors

• Disease state

  The physiochemical properties of the mucus are known to change during disease conditions such as the common cold, gastric ulcers, ulcerative colitis, cystic fibrosis, bacterial, and fungal infections of female reproductive tract and inflammatory conditions of the eye.

  Mucin turnover

  The mucin turnover is expected to limit the residence time of the mucoadhesives on the mucus layer. Second, mucin turnover results in substantial amounts of soluble mucin molecules.

Materials

The following drug, polymers, and chemicals were used for the formulation and evaluation of tablets.
List of solvents and chemical:

• Distilled water
• Methanol
• Acetone
• Concentrated hydrochloric acid
• Ammonium acetate
• Acetonitrile

Preformulation study7,8

Identification of drug

Identification of drug was carried out by melting point determination, infrared spectroscopy, and differential scanning calorimetry (DSC).

Melting point method

Melting point method is prime confirmation of drug. In this method, temperature was noted at which point sample start melt to finish. The melting point of MCN was measured and found to be in the range of 186-188°C. It was confirmed with the reported melting point of MCN, i.e., 182-186°C (Clark’s analysis, Vol. 2, 1282).

Fourier transform infrared (FTIR) spectroscopy

IR spectrum of the drug was measured in the solid state as potassium bromide dispersion. The bands (cm−1) have been assigned. An FTIR spectrum of miconazole nitrate was obtained using an FTIR spectrometer-430 (8400S, Shimadzu, Japan).

Melting point determination by DSC

The melting point of drug was determined using DSC. Thermograms for MCN were obtained using DSC (Cyrus-DSC Wipro GE DX-300, Perkin Elmer, USA).

Drug-excipient interaction study9

The drug-excipients interaction study was carried out by using FTIR and DSC.

FTIR spectroscopy

Infrared spectroscopy is used to predict possible drug-excipients interaction study. IR spectrum of drug was measured in the solid state as potassium bromide dispersion. The drug, polymers, and physical mixture were filled in pre-washed and dried ampoules and sealed with aluminum paper. The sealed ampoules were kept at 37 ± 0.5°C for 28 days in stability chamber (TH 90 G, Thermolab, Thane, India) (Table 3).

DSC10,11

Drug, polymers, and physical mixtures were filled in the pre-washed and dried ampoules and sealed. The sealed ampoules were kept at 37 ± 0.5°C for 28 days in stability chamber (Thermolab, Thane, India). At the end of 28 days, ampoules were removed from stability chamber and proceed for interaction study.

Analysis of drug12,13

Solubility study of MCN in different solvents

Drug solubility was determined by preparing saturated drug solutions in distilled water and buffer medium, maintained at 37 ± 0.5°C in a water bath, and continually shaken using mechanical shaker (RO- 123R, Remi Instruments, Mumbai, India) up to 24 h (Table 4).

Standard calibration curve of drug

Standard stock solution

Accurately weighed 10 mg of MCN USP was taken and transferred in 100 ml volumetric flask. Diluent (0.2 M ammonium acetate buffer:acetonitrile:methanol 20:30:50) was added to dilute the solution up to 100 ml. Table 2: List of equipments used with their make

Formulation of buccal tablet14,15

Mucoadhesive buccal tablets were prepared by a direct compression procedure (Table 5).

Evaluation of pre-compression parameters16,17

Drug and polymers were characterized for their physical properties such as particle size distribution, angle of repose, density, compressibility, and Hausner’s ratio. Results are shown in Table 6.

Particle size determination18,19

For many active substances, particle size has an impact on powder flow; content uniformity, and drug dissolution. To assure consistent product quality, the particle size of the API has been characterized (By Malvern mastersizer, Dry method). From the results obtained, the limits will be derived which will be routinely applied by the API manufacturer during analysis of drug (Table 7).

Angle of repose, density, compressibility index, Hausner’s ratio

Pre-compression parameters of tablets powder blends20,21 The tablet of optimized formula powder blend shows good flow property (angle of repose more than 30 and <35). Results are shown in Table 8.

Post compression parameters

Prepared tablets were evaluated for post compression parameters (Tables 9 and 10).

Swelling index

Table 11 shows swelling index of miconazole nitrate buccal tablet.

Ex vivo bioadhesion study

Table 12 shows ex vivo bioadhesion study of prepared miconazole nitrate buccal tablet.

In vitro drug release profile(shown in fig)

• In the pre-formulation study (compatibility study), compatibility of the excipients used in the formulation with drug was done by FTIR and DSC. Results of the compatibility study reveal that the drug was compatible with all excipients used in the formulation.
• Here, direct compression strategy found satisfactory for all formulation. Hence, direct compression strategy was adopted.
• Various physicochemical parameters such as content uniformity, thickness, weight variation, bioadhesive strength, surface pH, swelling study, and matrix erosion were evaluated.
• Among different trials with direct compression, trial F10 had satisfactory in-vitro dissolution profile in comparison to the innovator. Hence, these batches tablets were selected for the preparation of tablets.
• Stability study was carried out for the optimized formulation at 40° C/75% RH for 3 months. The result shows no significant change in physical and chemical parameter of the tablet; hence, the formulation was found to be stable.

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