Formulation and physico-chemical characterisation of novel films and wafers for mucosal drug delivery

Development of novel drug delivery systems has become a major research endeavour in the pharmaceutical industry. Drug administration via the traditional oral route (GIT) presents certain challenges including enzymatic and acid break down of labile drugs and first pass metabolism in the liver. The research reported in this thesis involved the development of solvent cast films and freeze-dried wafers for the potential delivery of drugs via the buccal mucosa. The formulations were prepared from two polymers (κ-carrageenan (CAR) 911 and poloxamer 407 (P407)), two types of plasticizers (glycerol (GLY)) and various grades of polyethylene glycol (PEG) using paracetamol (PM), ibuprofen (IBU) and indomethacin (IND) as model drugs. The investigations involved extensive evaluation/characterisation of the initial formulation components and their optimum combinations to obtain the desired formulation by employing various physico-chemical characterisation techniques. Texture analysis was used to investigate the tensile properties (percent elongation and elastic modulus) of the films, the resistance of the films upon stretching as well as the behaviour of the films during handling. In the case of the wafers, texture analysis was used to determine the compressibility as well as in vitro mucoadhesive characteristics. The stability of both the initial components and within the formulated films or wafers was studied using thermal analysis (HSM, TGA and DSC). Thermogravimetric analysis (TGA) was used to estimate the residual water content of both formulations. XRPD was used to assess the different forms (amorphous or crystalline) of the various components, including the model drugs. Scanning electron microscopy provided topographic information with regard to surface architecture of the films and wafers. The drug loaded films and wafers were further characterised for chemical stability of the drugs, after storage at room temperature for twelve months and drug dissolution profiles using simulated saliva as dissolution medium. The results of the preliminary development and optimization experiments showed that gels prepared with 2.5% (w/w) CAR 911, in combination with 4% (w/w) P407 and 5.5% (w/w) PEG 600 produced a flexible film with ‘ideal’ characteristics and was selected for drug incorporation. However, the concentration of PEG was increased to 6% (w/w) in the presence of 1.6% w/w PM, and 6.5% (w/w) PEG with 0.6% (w/w) IND and 0.8% w/w IBU (concentrations relative total drug weight of film matrix). The initial results from the wafers demonstrated that a flexible wafer, obtained by freeze-drying (incorporating an annealing step), could be produced from a gel containing 2% (w/w) CAR 911 in combination with 4% (w/w) P407 and 4.4% (w/w) PEG 600. Addition of 0.8% (w/w) IBU also increased the flexibility of the wafer approximately two fold, whilst the flexibility of 1.8% (w/w) PM and 0.6% (w/w) IND loaded wafers was slightly reduced. TGA experiments indicated a water content of approximately 5% and 1% for films and wafers, respectively. SEM experiments revealed an even surface without any macroscopic pores for the film whilst the microstructure of the wafer was observed as being porous. The data from DSC experiments demonstrated interactions between P407 and PEG 600 during film formation. Furthermore, the conversion of the originally added model crystalline drugs into the amorphous form within the film and wafers was ascertained by DSC and confirmed by XRPD

Improving drug loading of mucosal solvent cast films using a combination of hydrophilic polymers with amoxicillin and paracetamol as model drugs

Solvent castmucosal films with improved drug loading have been developed by combining carboxymethyl cellulose (CMC), sodium alginate (SA), and carrageenan (CAR) using paracetamol and amoxicillin as model drugs and glycerol (GLY) as plasticizer. Films were characterized using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), folding resilience, swelling capacity, mucoadhesivity, and drug dissolution studies. SA, CMC, and GLY (5 : 3 : 6) films showed maximum amoxicillin loading of 26.3% whilst CAR, CMC, and GLY (1 : 2 : 3) films had a maximum paracetamol loading of 40%. XRPD analysis showed different physical forms of the drugs depending on the amount loaded. Films containing 29.4% paracetamol and 26.3% amoxicillin showed molecular dispersion of the drugs while excess paracetamol was observed on the filmsurface when themaximum 40% was loaded. Work of adhesion was similar for blank films with slightly higher cohesiveness for CAR and CMC based films, but the differences were significant between paracetamol and amoxicillin containing films. The stickiness and cohesiveness for drug loaded films were generally similar with no significant differences. The maximum percentage cumulative drug release was 84.65% and 70.59% for paracetamol and amoxicillin, respectively, with anomalous case two transport mechanism involving both drug diffusion and polymer erosion

Development of polymeric films incorporating amorphous drug

Incorporation of amorphous drugs in formulations can help address current solubility challenges in drug delivery [1, 2]. The aim of the current study was to develop novel polymeric films for buccal drug delivery and to investigate their ability to incorporate and stabilize an amorphous drug

Formulation development of a carrageenan based delivery system for buccal drug delivery using ibuprofen as a model drug

Solvent cast films are used as oral strips with potential to adhere to the mucosal surface, hydrate and deliver drugs across the buccal membrane. The objective of this study was the formulation development of bioadhesive films with optimum drug loading for buccal delivery. Films prepared from κ-carrageenan, poloxamer and polyethylene glycol or glycerol, were loaded with ibuprofen as a model water insoluble drug. The films were characterized using texture analysis (TA), hot stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), x-ray powder diffraction (XRPD), high performance liquid chromatography (HPLC) and in vitro drug dissolution. Optimized films were obtained from aqueous gels containing 2.5% w/w κ-carrageenan 911, 4% w/w poloxamer 407 and polyethylene glycol (PEG) 600 [5.5% w/w (non-drug loaded) and 6.5% w/w (drug loaded)]. A maximum of 0.8% w/w ibuprofen could be incorporated into the gels to obtain films with optimum characteristics. Texture analysis confirmed that optimum film flexibility was achieved from 5.5% w/w and 6.5% (w/w) of PEG 600 for blank films and ibuprofen loaded films respectively. TGA showed residual water content of the films as approximately 5%. DSC revealed a Tg for ibuprofen at −53.87°C, a unified Tm for PEG 600/poloxamer mixture at 32.74°C and the existence of ibuprofen in amorphous form, and confirmed by XRPD. Drug dissolution at a pH simulating that of saliva showed that amorphous ibuprofen was released from the films at a faster rate than the pure crystalline drug. The results show successful design of a carrageenan and poloxamer based drug delivery system with potential for buccal drug delivery and showed the conversion of crystalline ibuprofen to the amorphous form during film formation

Development and physico-mechanical characterization of carrageenan and poloxamer-based lyophilized matrix as a potential buccal drug delivery system

Context and objectives: The buccal mucosa presents a unique surface for non-invasive drug delivery and also avoids first-pass metabolism. The objective of this study was the formulation development of polymeric mucoadhesive lyophilized wafers as a matrix for potential buccal drug delivery. Materials and methods: Differential scanning calorimetry (DSC) was used to develop an optimum freeze-cycle, incorporating an annealing step. The wafers were prepared by lyophilization of gels containing three polymers, κ-carrageenan (CAR 911), poloxamer (P407) and polyethylene glycol 600 (PEG 600). The formulations were characterized using texture analysis (for mechanical and mucoadhesion properties), hydration studies, thermogravimetric analysis (TGA), DSC, X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM). Results and discussion: DSC showed the eutectic temperature (12.8 °C) of the system where the liquid solution and pure solids both existed at a fixed pressure which helped determine the freeze-annealing cycle at 55 °C for 7 h. Mechanical resistance to compression, hydration and mucoadhesion studies showed that optimized wafers were obtained from aqueous gels containing 2% w/w CAR 911, 4% w/w P407 and 4.4% w/w PEG 600. TGA showed residual water of approximately 1% and SEM showed a porous polymeric network that made ease of hydration possible. Conclusions: Lyophilized wafers by freeze-drying gels containing 2% w/w CAR 911, 4% w/w P407 and 4.4% w/w PEG 600 with optimum physico-mechanical properties has been achieved

Lyophilized wafers comprising carrageenan and pluronic acid for buccal drug delivery using model soluble and insoluble drugs

Lyophilized muco-adhesive wafers with optimum drug loading for potential buccal delivery have been developed. A freeze-annealing cycle was used to obtain optimized wafers from aqueous gels containing 2% κ-carrageenan (CAR 911), 4% pluronic acid (F127), 4.4% (w/w) polyethylene glycol with 1.8% (w/w) paracetamol or 0.8% (w/w) ibuprofen. Thermogravimetric analysis showed acceptable water content between 0.9 and 1.5%. Differential scanning calorimetry and X-ray diffraction showed amorphous conversion for both drugs. Texture analysis showed ideal mechanical and mucoadhesion characteristics whilst both drugs remained stable over 6 months and drug dissolution at a salivary pH showed gradual release within 2 h. The results show the potential of CAR 911 and F127 based wafers for buccal mucosa drug delivery

Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs

Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w κ-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a Tg at 22.25 and 30.77°C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40 min of contact with dissolution medium simulating saliva