Mucoadhesive thermoreversible formulation of metoclopramide for rectal administration: a promising strategy for potential management of chemotherapy-induced nausea and vomiting.

The study aimed to investigate the feasibility of incorporation of metoclopramide hydrochloride (MCP HCl) in mucoadhesive thermoreversible liquid suppository (MCP HCl-LS) to bypass the first-pass metabolism and maximize its efficacy to be a promising substitute for parenteral therapy. MCP HCl-LS was formulated using Pluronic (PF127/PF68) and hydroxypropylmethylcellulose (HPMC) and in vitro evaluated through their gelation temperature, gel strength (GS), mucoadhesive force, and in vitro release studies. Also, the MCP HCl-LS was evaluated for its rheological behavior and examined for rectal mucosal integrity after administration. The results revealed that the MCP HCl-LS; composed of PF127/PF68/HPMC (20/7/0.5% w/w) was in the liquid state at room temperature, experienced gelation at 30.23 °C, with suitable GS of 28.66 s and rectal retention force of 43.03 × 102 dyne/cm2. The pharmacokinetic data showed that the MCP HCl-LS exhibited a significant increase (p < 0.05) in AUC0-480 (219.688 vs 172.333 ng.h.mL-1 of the marketed) and 1.3-fold increase in relative bioavailability compared to Primperan® suppository, indicating that LS formula bypassed the first-pass metabolism. Moreover, MCP HCl-LS did not cause any morphological harm to the rectal tissues suggested that the developed formulation was safe and could be a potentially useful alternative drug carrier for rectal delivery of MCP HCl in patients experiencing chemotherapy-induced nausea and vomiting.

Optimization and Evaluation of the Thermosensitive In Situ and Adhesive Gel for Rectal Delivery of Budesonide.

Budesonide is a glucocorticoid for the treatment of ulcerative colitis (UC). The current study aims to develop a thermosensitive in situ and adhesive gel for rectal delivery of budesonide. HPMC K4M was selected as the adhesive agent based on the adhesive force and the effect on gel performance. The formulation of gel was optimized by using the central composite design-response surface methodology (CCD-RSM); a mathematical model was successfully developed to predict desired formulations as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, and HPMC K4M and the performances of gel. Based on CCD-RSM, a thermosensitive in situ and adhesive gel consisting of 0.002% budesonide, 0.74% HPMC, 4.87% F-68, and 19.0% F-127 was developed. Furthermore, the in vivo behavior of gel was evaluated in Sprague-Dawley rats. In comparison with budesonide solution, rectal administration of budesonide gel at 0.1 mg/kg in rats showed relative bioavailability of 230% with significant increase in rectum uptake.

Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.

Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore, persistent and resurgent currents are likely to determine whether a mutation in Nav1.7 leads to IEM or PEPD.

Multifunctional nanobeacon for imaging Thomsen-Friedenreich antigen-associated colorectal cancer.

This research aimed to validate the specificity of the newly developed nanobeacon for imaging the Thomsen-Friedenreich (TF) antigen, a potential biomarker of colorectal cancer. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a Coumarin 6 dye. The surface of the nanosphere was modified with peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-ß(1-3)GalNAc with high affinity while the latter enhances the specificity of PNA for the carbohydrates. The specificity of the nanobeacon was evaluated in human colorectal cancer cells and specimens, and the data were compared with immunohistochemical staining and flow cytometric analysis. Additionally, distribution of the nanobeacon in vivo was assessed using an "intestinal loop" mouse model. Quantitative analysis of the data indicated that approximately 2 µg of PNA were detected for each milligram of the nanobeacon. The nanobeacon specifically reported colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA. Removal of TF from human colorectal cancer cells and tissues resulted in a loss of fluorescence signal, which suggests the specificity of the probe. Most importantly, the probe was not absorbed systematically in the large intestine upon topical application. As a result, no registered toxicity was associated with the probe. These data demonstrate the potential use of this novel nanobeacon for imaging the TF antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer at the molecular level.

Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories.

The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.

Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men.

BACKGROUND: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. METHODS: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. RESULTS: SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). CONCLUSIONS: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. CLINICAL TRIALS REGISTRATION: NCT00775294.

A novel administration route of edaravone--II: mucosal absorption of edaravone from edaravone/hydroxypropyl-beta-cyclodextrin complex solution including L-cysteine and sodium hydrogen sulfite.

We examined the pharmacokinetics of edaravone when edaravone/hydroxypropyl-beta-cyclodextrin (HPbetaCD) complex solution, including L-cysteine (L-Cys) and sodium hydrogen sulfite (SHS), was administered intravenously, rectally and via the oral mucosa. In oral mucosal administration, atomized edaravone/HPbetaCD complex solution that contained L-Cys and SHS was sprayed into the mouth of Wistar rats. Oral mucosal and rectal administration of edaravone/HPbetaCD complex solution that contained L-Cys and SHS was compared with that for edaravone/HPbetaCD complex solution without L-Cys and SHS. When edaravone 0.25-1.0 mg was administered intravenously, C(0) and AUC(0-60) were linear. In oral mucosal and rectal administration, C(max) and AUC(0-60) of edaravone/HPbetaCD with L-Cys and SHS were significantly higher than those of edaravone/HPbetaCD without L-Cys and SHS. On the other hand, bioavailability of oral mucosal, rectal and oral administration was about 100, 63.5 and 26.6%, respectively. This study suggested that L-Cys and SHS were useful for the oral mucosal and rectal administration of edaravone.

New tools to design smart thermosensitive hydrogels for protein rectal delivery in IBD.

Local treatment of Inflammatory Bowel Disease (IBD) has been pointed out to be a novel therapeutic approach with several advantages when compared to conventional therapies. However, the development of systems able to fulfil the requirements of this administration route is not an easy task. The present work suggests the utilization of Artificial Intelligence Tools (AIT) as an instrument to understand polymer-polymer interactions towards obtaining thermosensitive hydrogels suitable for protein rectal administration in IBD. Enemas composed by Pluronic® F127 and F68 and Methocel® K4M were developed and characterised. Two experimental designs were carried out in order to determine the effect of each polymer on their texturometric and rheological behaviour. Using the results of the first experimental design we can justify the inclusion of each raw material PF127, PF68 and MK4M in the formulation and conclude that a compromise solution is necessary to obtain thermosensitive hydrogels of the required properties. The results of the second experimental design allowed concluding that PF127 ruled mainly syringeability and bioadhesion work. On the other hand, PF68 modulated principally gelation temperature, viscosity and protein release from hydrogel matrix. Finally, MK4M influenced bioadhesiveness and mostly determined viscosity. AIT also allowed delimiting the design space to produce easy administrable and highly bioadhesive enemas that undergo fast sol-gel transitions at body temperature.

Colorectal distribution and retention of polymeric nanoparticles following incorporation into a thermosensitive enema.

Nanotechnology-based systems have been proposed for rectal drug delivery, often rendering promising outcomes concerning disease prophylaxis or therapeutics. However, nanocarriers often feature reduced colorectal retention when administered in liquid vehicles (enemas). Semi-solid platforms may be considered as alternative but usually result in limited local distribution. Thermosensitive enemas undergoing sol-gel transition just below body temperature have been used for abbreviating these issues, but the actual impact on the colorectal distribution and retention of incorporated nanosystems is not clear. We prepared and characterized a potential drug delivery platform by incorporating poly(lactic-co-glycolic acid)-based nanoparticles (170-180 nm mean hydrodynamic diameter) into a poloxamer 407-based thermosensitive enema (NPs-in-thermo). The system featured suitable functional properties for rectal administration such as sol-gel transition temperature of approximately 27-28 °C, sol-gel transition time of 1.6 min, and viscosity around 31 and 2100 mPa s at 20 °C and 37 °C, respectively. NPs-in-thermo presented osmolality and pH values deemed compatible with the colorectal compartment, as well as reduced toxicity to the Caco-2 colorectal cell line. The composite system was also used to incorporate the anti-HIV microbicide model drug dapivirine. In vitro studies showed that dapivirine-loaded NPs-in-thermo was able to provide overall faster drug release as compared to dapivirine directly dispersed into phosphate buffered saline or the thermosensitive enema base. Finally, NPs-in-thermo was tested for distribution and retention in a mouse model by in vivo and ex vivo near infrared imaging. Qualitative and semi-quantitative data indicated that NPs exhibited slower but overall wider distribution and enhanced retention in the distal colon of mice treated intrarectally with NPs-in-thermo, namely when compared to NPs dispersed in liquid phosphate buffered saline. Overall, our data support that thermosensitive enemas may provide suitable platforms for the rectal administration of polymeric NPs, namely in the context of drug delivery.

Surface modification with polyethylene glycol enhances colorectal distribution and retention of nanoparticles.

Dense surface modification with short chain polyethylene glycol (PEG) has been previously demonstrated as favoring the transport of nanoparticles (NPs) across mucus. However, the ability of such approach to influence the distribution and retention of NPs along the length of the colorectum after rectal delivery has not been previously established. Herein, the distribution and retention of poly(lactic-co-glycolic acid) NPs modified with PEG in a non-covalent fashion are reckoned in a mouse model. Despite overall rapid depletion, both PEG-modified and non-modified NPs are able to reach the middle segment of the colon. PEG-modified NPs are able to enhance retention up to at least two hours post-administration, contrasting with nearly residual levels observed for non-modified NPs after 15 min. The ability of PEG-modified NPs to putatively cross mucus also appears to promote association with tissues. Overall, the work provides significant insights as to the behavior of NPs in the colorectum, which could be valuable for the development of rectal nanomedicines. It further reinforces the potential usefulness of PEG-modified NPs as mucus-penetrating carriers for mucosal drug delivery.

Reciprocating dialysis tube method: periodic tapping improved in vitro release/dissolution testing of suppositories.

The reciprocating dialysis tube (RDT) method can be used for in vitro release/dissolution testing of suppositories and has been reported to show good in vitro and in vivo correlation. However, for suppositories with viscous excipients, the result remains variable and generally under-predicts in vivo absorption. The purpose of this study was to assess whether periodic tapping of the closure of the RDT could improve in vitro release testing of suppositories. Two commercially available acetaminophen suppositories (A and B) that showed characteristic release behavior under normal rectal temperatures (37 and 38 degrees C) were chosen as test suppositories. In the absence of tapping, suppository A showed different release profiles at 37 and 38 degrees C, but the difference disappeared with periodic tapping. This finding was consistent with minimum temperature effect in the rectal absorption of suppository A in rabbits. Suppository B showed distinct release profiles at 37 and 38 degrees C irrespective of tapping, and the rectal absorption of suppository B in rabbits was affected by temperature. The test variability (CV% and ranges of release values) was substantially reduced in the presence of tapping. In conclusion, the addition of periodic tapping to RDT method developed in this study could improve in vitro release testing of suppositories.

Thermally reversible in situ gelling carbamazepine liquid suppository.

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo.

AIM: We previously reported that nanoparticles (NPs) coated with 10 kDa PEG were mucoadhesive. Here, we demonstrate that by increasing the surface density, PEG with molecular weight (MW) as high as 40 kDa can be used as a mucoinert NP surface coating. MATERIALS & METHODS: We compared two sets of reaction conditions for coating model polystyrene NPs with 10 kDa PEG and used optimized conditions to coat NPs with PEG as high as 40 kDa in MW. We then characterized NP transport in human cervicovaginal mucus ex vivo. We further administered PEG-coated NPs to the mouse cervicovaginal tract and colorectum to assess mucosal distribution in vivo. RESULTS & CONCLUSION: We demonstrate here that PEG with MW as high as 40 kDa can be densely grafted to the surface of NP to prevent interactions with mucus. NP coated with 10-40 kDa PEG rapidly diffused through human cervicovaginal mucus ex vivo, and uniformly lined the mouse colorectal and vaginal epithelium in vivo.

Permeability study of ciprofloxacin from ultra-thin nanofibrous film through various mucosal membranes.

Permeability plays an important role to achieve the desired therapeutic outcomes. Present study was designed to investigate the permeability of ciprofloxacin from ultrathin polyvinyl alcohol nanofiber through different biological membranes. Results of the permeability studies indicated that nanofibers exhibit higher drug permeability than plane drug. Intestinal tissue shows maximum permeability followed by eye, trachea, sublingual, rectal, and skin. Permeability studies also inferred a steady-state release of drug of the nanofiber, whereas a high degree of fluctuations was observed in plane drug. Nanofiber being 2D nanoscale material provides numerous advantages to be used as an encapsulated carrier system to improve the therapeutic effectiveness.

A theranostic micelleplex co-delivering SN-38 and VEGF siRNA for colorectal cancer therapy.

The development of an efficient colorectal cancer therapy is currently a public health priority. In the present work, we proposed a multifunctional theranostic micellar drug delivery system utilizing cationic PDMA-block-poly(ε-caprolactone) (PDMA-b-PCL) micelles as nanocarriers of SN-38 (7-ethyl-10-hydroxycamptothecin), ultra-small superparamagnetic iron oxide nanoparticles (USPIO), and small interfering RNA (siRNA) that targets human vascular endothelial growth factor (VEGF). The VEGF siRNA was conjugated to polyethylene glycol (PEG) (siRNA-PEG) before complexation with the micelles in order to improve the siRNA's stability and to prolong its retention time in the blood circulation. To further improve the in vivo biosafety, we prepared mixed micelles using mPEG-PCL together with PDMA-b-PCL copolymer. The SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes passively targeted to tumor regions and synergistically facilitated VEGF silencing and chemotherapy, thus efficiently suppressing tumor growth via a multi-dose therapy regimen. Additionally, the SN-38/USPIO-loaded siRNA-PEG mixed micelleplexes acted as a negative magnetic resonance imaging (MRI) contrast agent in T2-weighted imaging, resulting in a powerful tool for the diagnosis and for tracking of the therapeutic outcomes. In summary, we established a theranostic micellar drug and gene delivery system that not only synergistically combined gene silencing and chemotherapy but also served as a negative MRI contrast agent, which reveal its potential as a novel colorectal cancer therapy.

Enhanced rectal absorption of [Asu1,7]-eel calcitonin in rats using polyacrylic acid aqueous gel base.

The effects of polyacrylic acid aqueous gel on the absorption of rectally administered [Asu1,7]-eel calcitonin, a calcitonin analogue, were investigated in rats. The [Asu1,7]-eel calcitonin (1 U/kg) was given into the rectal loop in gel bases at various pH (5.5-8.5) and polyacrylic acid concentrations (0.01-1.0% w/v). The maximum hypocalcemic effect was obtained in approximately 30 min after administration of the analogue in a 0.1% w/v polyacrylic acid gel base at pH 5.5. The plasma calcium level decreased by approximately 18% from the initial level. Rectal administration in vehicles such as polyethylene glycol 1000, triglyceride fatty acid mixture base, or saline solution had little or no hypocalcemic effect at a dose of 5 U/kg. The results indicated that a polyacrylic acid aqueous gel base significantly improved the absorption of this analogue. Furthermore, rectal administration in a polyacrylic acid gel base (0.1% w/v; pH 5.5) required a dose 35 times greater than an intravenously administered dose to achieve an equivalent hypocalcemic effect.

Characterization of the barrier properties of mucosal membranes.

The barrier properties of the nasal, rectal, and vaginal membranes were investigated in the rabbit by comparing physical characteristics and permeability to model hydrophilic and lipophilic compounds. It was found that the nasal, rectal, and vaginal mucosae differ in their physical characteristics and interactions. The nasal mucosa had the highest in vitro transport of both the model hydrophilic compound, mannitol, and the model lipophilic compound, progesterone. Although the nasal mucosa was found to have some hydrophilic character, it appears that these mucosae are primarily lipophilic in nature. The role of the lipid domain in the barrier properties of these mucosal membranes was investigated using progesterone and a series of its hydroxyprogesterone analogues. Membrane permeability was found to decrease as the order of hydrophilicity of the progestins increased, indicating that the lipid domain plays an important role in the barrier function of these membranes. The changes observed in the physical properties and permeability of the mucosal membranes after extraction of the lipids also demonstrated the importance of the lipid domain in the maintenance of the mucosal barrier.

Preparation and evaluation of Eudragit gels. VIII. Rectal absorption of 5-fluorouracil from Eudispert hv gels in rats.

Rectal absorption of the hydrophilic 5-fluorouracil (5-FU) in rats was studied with Eudispert hv gels with or without fatty acids as the rectal bases. In the absence of fatty acids, absolute bioavailabilities of 5-FU for Eudispert hv hydrogel and xerogel preparations increased approximately 2.5 times compared with those of Witepsol H-15 and PEG 2000 suppositories. When n-capric acid or linolenic acid was used as an absorption enhancer, absolute bioavailabilities of 5-FU were, respectively, 25.5 and 30.9% for Witepsol H-15 and 64.4 and 66.1% for PEG 2000. Furthermore, the absolute bioavailabilities of 5-FU for Eudispert hv hydrogel with n-capric acid or linolenic acid were 95.6% and 81.7%. The addition of capric acid or linolenic acid to the hydrogel was a useful method for increasing 5-FU permeability through the rectal membranes. These results are consistent with the observation that the total amounts of 5-FU remaining in the lumenal contents of the rectum and that accumulated in the rectal tissue decreased in relation to the increase in the bioavailabilities. Thus, the Eudispert hv hydrogel containing 5-FU with capric acid may be a useful rectal preparation for increasing the maximum plasma level and improving the absolute bioavailability of 5-FU.

Rectal bioavailability of water-soluble drugs: sodium valproate.

The influence of adjuvants in suppository formulations on the release and absorption of sodium valproate, a water soluble anti-epileptic, was analysed in order to determine the optimal formula for rectal administration. Three formulations were prepared with Suppocire AS2(formula I), Aerosil R 972 (formula II) or Span 80 (formula III). In-vivo and in-vitro release-diffusion studies were performed using white laboratory rabbits as the experimental model. The adjuvants decreased the percentage release of valproic acid to 96.7% (formula I) and 84.1% (formula II), and delayed peak release-diffusion concentration (210 and 150 min, respectively, with formulas II and III in comparison with 120 min with formula I). Their effect on bioavailability was observed as an increase in plasma levels of the active substance, with areas under the plasma concentration/time curve of 396.26 and 306.64 micrograms h mL-1 (formulas II and III, respectively) and 243.28 micrograms h mL-1 (formula I). The time to peak plasma concentration was also delayed with peaks at 30, 55 and 50 min with formulas I, II and III, respectively.

Effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin in rats.

The effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin, a calcitonin analogue, was studied in rats. Absorption was enhanced by a microenema which used a polyacrylic acid gel base, but it was reduced by the incorporation of polysorbate 80 (0.1-5% v/v). The incorporation of polyoxyethylene 9 lauryl ether (0.1-5% v/v) in the polyacrylic acid gel base enhanced the absorption. Rectal administration in the base containing 0.5% v/v polyoxyethylene 9 lauryl ether required a dose of the calcitonin 2-3 times greater than an intramuscularly administered dose to achieve an equivalent hypocalcaemic effect.