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Michael J. Rathbone et al., 1994 highlighted the advantages of systemic drug delivery via the oral mucosa and discussed about the membrane, drug, dosage form and environmental issues which affects its use as a site for systemic drug delivery.
Amir H. shojaei et al., 1998 mainly discussed about the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug absorption/permeation. And finally concluded that buccal mucosa offers several advantages for controlled release drug delivery for extended periods of time. The Buccal area is well suited for a retentive device and appears to be good enough by the patient. But, the need for safe and effective buccal permeation/absorption enhancers is a important factor for a forthcoming future in the area of buccal drug delivery.
PriyaBatheja discussed in chapter Basic Biopharmaceutics of Buccal and Sublingual Absorption about oral mucosal route, which might be the potential option for drug delivery and for macro- and micro molecular deliveries. Administered peptides still remain susceptible to the permeability and enzymatic barrier of the buccal mucosa, and in many studies only moderate bioavailability has been observed. The advent of techniques like enzyme inhibitors, effervescent tablets, mucoadhesive devices, and absorption enhancers along with other advantages such as patients acceptability and low degradation have initiated numerous studies for delivery of proteins and peptides by this route.
Attwood,D et al.,2000 formulated and evaluated sustained release diltiazem sublingual single-layered and bilayered tablets containing 1:4,1:1 and 4:1 weight ratios of pectin and hydroxyl propyl methyl cellulose(HPMC) by using direct compression technique and ethylcellulose was used as backing layer in bilayered tablet. Measurements of maximum adhesion force to rat peritoneal membrane indicated a satisfactory bioadhesive strength for different weight ratios of pectin and HPMC were 28.9±4.3, 42.3±7.2 and 66.0±4.0, respectively (n=6). From the invitro release studies it was found that , the bilayered tablets had shown prolonged as compared to that of single layered tablets of pectin/HPMC (1:1). From the plasma concentration time curves it was found that , single and bilayered tablets shows sustained effect as compared with oral. Bioavailability of single layered diltiazem tablet was 2.5 times more than of oral, where as in case of bilayered it was 1.8 times. The bioavailabilityofdiltiazem calculated from the ratio AUC[(oral/i.v)x100] were 75.4% for single layered tablets, 54.5% for bilayered tablets and were compared with the oral bioavailability value[30.4%] and concluded that single and bilayered has more bioavailability.
Doherty,JR.et al.,2002 investigated and developed transmucosal drug delivery system for delivery of phosphodiesterase inhibitors for the treatment of erectile dysfunction using different modes of administration include transbuccal, sublingual and transrectal routes.
Chister Nystrom et al., 2003 developed and introduced a new tablet form for sublingual administration. The tablet is prepared by mixing interactively the excipients, consisting of carrier particles partially covered by fentanyl citrate drug particles. In the interests of increasing retension of the drug molecule at the site of drug absorption in the oral cavity, a bioadhesive ingredient was also added to the carrier material, cross-linked polyvinyl pyrrolidone was used as the disintegrant and bioadhesive component. Tablets containing 100,200 and 400μg of fentanyl citrate were disintegrated and the results obtained were 10 seconds and 33-50 seconds, without discs and with discs. From the invitro dissolution studies it was found that the fentanyl citrate was released from the formulations containing 100,200μg,75% release obtained within 1 min. Whereas in 400μg fentanyl tablets dissoluion was slightly slow. The dissolution rate is not influenced upon the compaction of the ordered units. From the pharmacokinetic studies, after single dose administration, plasma concentrations of fentanyl were obtained within 10min. The Area under the plasma Concentration-Time curves(AUC) of Sublingual dosage form is compared with intravenous form, at least 70% of the doses administered, reached the systemic circulation.
R.C.Mashru et al.,2005 developed and investigated Fast-Dissolving Film of Salbutamol Sulphate,which can be useful in an acute attack of asthma. The film was prepared using a solvent evaporation technique and was administered through the sublingual route. The Sublingual film contains polyvinyl alcohol as a polymer, glycerol as a plasticizer, and mannitol as filler. A 33 full factorial design was utilized for the optimization of the effect of independent variables such as amount of polyvinyl alcohol, amount of glycerol, amount of mannitol on the mechanical properties, and % drug release of film . The multiple regression analysis has been conducted on the results obtained leads to describe adequately about the influence of the independent variables on the selected responses. Polynomial regression equations and contour plots were used to relate the dependent and independent variables. The experimental results indicated that polymer concentration, plasticizer concentration, and filler concentration had complex effects on film mechanical behavior and % drug release. Furthermore, the desirability function was employed in order to determine the best batch out of all 27 batches of the factorial design. The % relative error was calculated, which showed that observed responses were in close agreement with the predicted values calculated from the generated regression equations. It was found that the optimum values of the responses for fast release film could be obtained at medium levels of polyvinyl alcohol and glycerol, and a high level of mannitol. The prepared film was clear, transparent, and had a smooth surface. The concept of similarity factors Sd was used to prove similarity of dissolution between distilled water and simulated saliva (pH 6.8) or simulated gastric fluid (pH 1.2).
MutasemM.Rawas-Qalaji et al., 2006 studied and investigated the effect of enhancing epinephrine load on the uniqueness of fast-disintegrating sublingual tablets for potential emergency treatments of anaphylaxis. Four tablet formulations, A,B,C and D, containing 0%, 6%, 12% and 24% of epinephrine bitartrate, respectively and microcrystalline cellulose : low-substituted hydroxypropyl cellulose (9:1) were used, and were prepared by direct compression, at a varying range of compression forces. Tablet hardness, disintegration time, friability, weight variation, content uniformity and wetting time were measured for formulations at each compression force. A proportional enhancement in compression force resulted in an exponential increase in hardness for all formulations, a linear enhancement in disintegration and wetting time of formulation A, and an exponential increase in wetting time and disintegration of formulations B, C and D. At a mean ±SD hardness of ≥2.3±0.2 kg, all formulations passed the USP friability test. At a mean ±SD hardness of ≤ 3.1±0.2kg, all formulations resulted in disintegration and wetting times of less than 10 seconds and less than 30 seconds, respectively.
Peter,A,crooks.et.al., 2006 formulated a sublingual spray drug delivery system of oxycodone and investigated the effect of formulation pH on sublingual absorption of oxycodone for acute pain management by using rabbit as a animal model. By using a new, specific and sensitive liquid chromatography/mass spectroscopy (LC/MS) with electrospray ionization detector, the bioavailability of sublingual oxycodone was determined in rabbits by comparing plasma concentration after sublingual spray delivery with that of equivalent intravenous dose. The effect of formulation pH on sublingual absorption of oxycodone was also performed on rabbits that had received oxycodone through sublingual route at a dose of 0.1 mg/0.1 mL (pH 4.0 and 9.0). Blood samples were collected at different time points, and plasma oxycodone concentrations were determined by LC/MS. Following administration of a 0.1 mg dose, the average Cmaxvalues were found to be 5807.0, and 8965.3ng.min/mL for formulation pH 4.0 and 9.0, respectively. The mean sublingual bioavailability of oxycodone was estimated to be 70.1%±17.9% and 45.4%± 20.1% for pH 4.0 and 9.0 respectively. No significant affect on formulation bioavailability (p<0.05). A sublingual spray dosage form of oxycodone hydrochloride would be a good choice for fast onset pain management, particularly in children.
Oury et al.,2006 investigated and developed sublingual coated tablet of fentanyl. Fentanyl tablet is first compressed using tableting machine PR12 equipped punches of diameter 5.5mm and with the excipients Emcompress, Avicel PH200, Magnesium stearate. The compressed core tablet is then coated in two steps, first the suspension in water of fentanyl citrate and opadry II yellow is sprayed on to the core tablet in a drilled pan Trislot. Second step is disodium phosphate together with PEG6000 is sprayed on the just obtained coated fentanyl tablet. A crossover single-Dose comparative Bioavailability study of tablets prepared versus Actiq© 0.4mg in healthy male volunteers under fasting conditions were conducted and justified by the pharmacokinetic parameters AUC, Cmax,tmax that improved pharmacokinetics and highly enhanced bioavailability has been observed in comparison to the reference product(Actiq©)
Stephan Krahenbuhl et al.,2007 studied on new application of furosemide through sublingual route by conducting crossover studies on eleven healthy male volunteers. And compared the pharmacokinetics and pharmacodynamics of sublingual furosemide by administration in oral and i.v route as control. Higher bioavailability has been observed through sublingual route. Excretion of Sodium was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs 1.4 mmol min-1 , PË‚0.05), whereas urine volume did not differ significantly between the two application modes. In comparison, intravenous administration showed the expected more rapid and intense response. Sublingual administered furosemide tablets differ in certain kinetic and dynamic properties from identical tablets given orally. Sublingual administration of furosemide may offer therapeutic advantages in certain groups of patients.
NoushinBolourtchain et al.,2008 developed and optimized a sublingual tablet formulation of captopril which is an effective drug in the treatment of hypertension. Captopril containing sublingual tablets were prepared by direct compression method using different ingredients such as polyvinyl pyrrolidone, starch 1500, sodium starch glycolate and lactose (independent variables) and magnesium stearate, talc and aspartame (fixed components). Tablets were evaluated for the physical properties including hardness, disintegration tome and flexibility which were considered as responses in a D-optimal experimental plan. The obtained results were examined statistically using special cubic model and polynomial mathematical equations and found to be statistically significant (p<0.05) for disintegration time and friability data. Linear model was best fitted with hardness data. The obtained results were used to generate optimized over lay plot. The physical data from the numerical optimization were verified and found to be very close to those predicted from the regression analysis. Additional experiments including drug content, in vitro drug dissolution rate ane accelerated stability studies were also performed on the optimum formulation. All results obtained were satisfied and according to the requirements of a sublingual tablet.
MalgorzataSznitowska et al.,2008 investigated fast disintegrating sublingual tablets containing nitroglycerin either complex with β-cyclodextrin (NTG-CD) or titrated with crosspovidone(NTG-CP)were prepared using starch 1500 or starlac as disintegrants. Regarding disintegration time and stability of the active substance starch 1500 was more appropriate for NTG-CD while for NTG-CP sttarlac was wuitable. Stability of NTG was better in NTG-CD tablets than in NTG-CP tablets. However , within 12 months of storage at 25oc the loss of NTG in all formulations was still greater than 10%.
Sheeba F. R.et.al., 2009 studied and evaluated the effect of increasing nifedipine load on the characteristics of fast-disintegrating sublingual tablets for the potential emergency treatment of anginal pain and hypertension. Nifedipine undergoes first pass metabolism in liver and gut wall which has oral bioavailability of 43-77%. Sublingual dosage form bypasses the metabolism of the nifedipine in liver and offers a fast relieve from anginal pain and hypertension. An attempt has been made to prepare fast dissolving tablets of nifedipine using super distintegrants like croscarmellose sodium, sodium starch glycolate, crospovidone. Three different groups of formulations (A, R, and V) with variation in tablet excipients were prepared by direct compression method. Tablet weight variation, hardness, friability, drug content, disintegration time and dissolution time were evaluated for each formulation and found satisfactory. The studied sublingual tablet group V shows a lesser T50% compared to commercial oral tablet. The Group V also indicates the fast dissolution and disintegration rate of the optimized nifedipine sublingual tablet, which is prerequisite for rapid management of anginal and hypertension diseases.
Noushin bolourchian.et.al,( 2009) has designed and optimized a sublingual tablet formulation of physostigmine salicylate, an effective drug in Alzheimer's disease and nerve gas poisoning, by means of the D-optimal experimental design method. Polyvinyl pyrrolidone, lactose, starch 1500 and sodium starch glycolate were used in the formulations as independent variables. Tablets were prepared by the direct compression method and evaluated for their physical properties (tablet hardness, disintegration time and friability), which were regarded as responses in a D-optimal design.Response surface plots were plotted to study the tablet properties and the optimized overlay plot was generated based on the results. After verification of the optimum checkpoint formulations, an optimized formulation was chosen due to its desirable physical properties and closely observed and predicted values. Drug assay, content uniformity of the dosage unit, drug dissolution and accelerated stability studies were performed on the optimized formulation as further experiments. All the obtained results complied with the requirements of a sublingual tablet formulation.
Alan Lankford et al., 2009 formulated and evaluated Sublingual zolpidem tartrate (SZT) lozenge for treatment of insomnia at low dose. Pharmacokinetic studies has done and suggested that this formulation produces higher drug plasma levels within the first 15-20 min after dosing than the standard oral tablet using only approximately 30% of the standard dose. Published data suggested that SZT is generally safe and effective at rapidly inducing sedation without residual next-day effects, as long as the patient has at least 4 h remaining in bed at the time of administration. SZT is currently being reviewed by the US FDA for potential approval for insomnia characterized by middle-of-the-night awakenings with difficulty returning to sleep.
Koland,M.et.al., 2010 formulated and investigated fast dissolving films of ondansetron hydrochloride for sublingual administration. Sublingual films were prepared from polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carbopol 934p in different ratios by solvent casting method. PEG 400 or Propylene glycol as plasticizers and mannitol or sodium saccharin as sweeteners were also included. The IR spectral studies showed no interaction between drug and polymer or with other additives. Acceptable results were obtained when subjected to physico-chemical tests such as uniformity of weight, thickness, surface pH, folding endurance, uniformity of drug content, swelling index, bioadhesive strength and tensile strength. Sublingual Films were also subjected to in vitro drug release studies by using USP dissolution apparatus. Ex vivo drug permeation studies were also conducted using porcine membrane model. In vitro release studies indicated 81-96% release within 7 min and 66-80% within 7 min during ex vivo studies. Drug permeation of 66-77% was observed through porcine mucosa within 40 min. Higher percentage of drug release was observed from films containing the sweetener. The stability studies were performed for a period of 8 weeks and showed no significant change in drug content, surface pH and in vitro drug release.
Staner ,C et.al.,2010 compared zolpidem marketed formulation(Edluar) 10mg with that of oral formulation (Ambient)10mg by polysomnography (PSG) in patient with primary insomnia with primary objective was to compare the two formulations on sleep induction, measured by latency to persistent sleep (LPS), sleep onset latency (SOL) and latency to stage 1 (ST1L). Conducted randomized, double-blind, two-period, cross-over multi-centre studies in which each period comprised two successive PSG recording nights. After starting the PSG recording, treatment was began. Subjective sleep and residual effects were assessed the next morning. Seventy female and male patients aged 19-64 were analyzed in this studies. Sublingual zolpidem significantly shortened LPS by 34% or 10.3 minutes as compared to oral zolpidem (95% CI: −4.32009min to −16.22009min, p2009=20090.001). SOL and ST1L were also significantly shortened (p2009<20090.01). Furthermore the two formulations were comparable in terms of sleep maintenance properties based on total sleep time (TST). The improvement in subjective sleep and next-day residual effects did not differ between the two treatments. Both routes of administration were well tolerated. The results shows that sublingual zolpidem was better to an equivalent dose of oral zolpidem in terms of sleep inducing properties in a carefully selected sample of primary insomnia patients.
Didier,A et.al., 2007 studied and assessed the safety, efficacy and optimal dose of grass pollen tablets for immunotherapy of patients with allergirhinoconjunctivitis. Arandomized, doluble-blind, Placebo- controlled studies were performed on 628 adults with grass pollenrhinoconjunctivitis( this is confirmed by conducting positive skin prick test and serum-specific IgE) received 1 of 3 doses of a standardized 5-grass pollen extract, and placebo also been performed , given through sublingual route (once-daily). The treatment was performed for 4 months during the pollen season. The primary outcome was Rhinoconjunctivitis Total Symptom Score; secondary outcomes included 6 individual symptom scores, rescue medication use,quality of life, and safety assessments. Both the 300-index of reactivity (IR) and 500-IR doses significantly reduced mean Rhinoconjunctivitis Total SymptomScore (3.58 6 3.0, P 5 .0001; and 3.74 6 3.1, P 5 .0006, Respectively) compared with placebo (4.93 6 3.2) said that there is a significant difference in the score.Where as the 100-IR group (4.70 63.1) score was not significantly different from placebo. Analysis of all secondary efficacy variables (sneezing, runny nose, itchynose, nasal congestion, watery eyes, itchy eyes, rescuemedication usage, and quality of life) confirmed the efficacy of the 300-IR and 500-IR doses. No serious side effects were reported. In the first pollen season, the efficacy and safety ofsublingual immunotherapy with grass tablets was confirmed.The 300-IR and 500-IR doses both demonstrated significant efficacy compared with placebo.
ElinaTurunen et.al.,2010 formulated and investigated Fast dissolving sublingual perphenazine tablet by complexation(solid dispersion) with β-cyclodextrin and macrogel 8000. Absorption studies were performed in rabbits , after sublingual administration of perphenazine/macrogol solid dispersion, solid perphenazine/β-CD complex and plain micronized perphenazine, as well as after peroral administration of an aqueous perphenazine solution. Solid formulations were prepared by freeze-drying (perphenazine/macrogol solid dispersion) or spray-drying (perphenazine/β-CD complex). The value for area under the curve from 0 to 360 min (AUC0-360 min) of perphenazine after peroral administration was only 8% of the AUC0-360 min value obtained after intravenous administration, while the corresponding values for the sublingually administered formulations were 53% (perphenazine/macrogol solid dispersion), 41% (perphenazine/β-CD complex) and 64% (micronized perphenazine). There are three possible mechanisms to explain these results: avoidance of the first-pass metabolism; good sublingual absorption of perphenazine; and rapid dissolution rate of perphenazine from the studied formulations. With sublingual administration, the drug has to dissolve rapidly in a small volume of saliva. Based on the present absorption studies in rabbits, the solid dispersion preparation and cyclodextrin complexation were postulated to be useful ways to attain successful sublingual administration of perphenazine. Good sublingual absorption was also achieved by micronization of perphenazine. As far as we are aware, this paper is one of the first to evaluate the sublingual administration of a solid dispersion in vivo.