Propylene Glycol Formulations Research Articles

Liposomal Cyclosporine A (L-CsA) via Inhalation to Treat Bronchiolitis Obliterans Syndrome: Novel Formulation and Drug-Specific Delivery System Improves Tolerability

Purpose Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term benefit after lung transplantation. There is no therapy with demonstrated benefit. As BOS is a T-cell mediated process, cyclosporine A given topically to the airways is a good candidate molecule but is highly insoluble. Characteristics of a liposomal formulation (L-CsA) is compared to a propylene glycol formulation (CsA-PG) are presented here. Methods Retrospective comparison of in vitro data and clinical data from prospective randomized clinical trials. CsA-PG (62.5 mg/mL) dosed 300 mg/5 mL three times weekly was compared to L-CsA (lyophilisate reconstituted with 0.25% saline) in a final concentration of 5 mg/1.25mL or 10 mg/2.5mL per twice daily. CsA-PG was delivered by a Sidestream Disposable nebulizer and use of a Mobilaire compressor; L-CsA was delivered via a PARI investigational eFlowr specifically designed for use with L-CsA. (L-CsA eFlow). Results Pharmacokinetic models predict a constant drug level in the lung with twice daily inhalation of L-CsA as compared to 3-times weekly inhalations of CsA-PG which resulted in high peak and low trough levels. Serum level of L-CsA was 57.42 ± 34.26 ng/mL; trough level was 4-5 ng/mL. Inhalation time was mean 60 min for CsA-PG 300mg, 6-10 min for L-CsA 5mg and 8-13 min for L-CsA 10mg dose. Tolerability data is assessed from 373 patient-month drug exposure to CsA-PG and 1068 patient-month exposure to L-CsA. Premedication was not used with L-CsA, whereas premedication with lidocaine and albuterol was necessary to improve tolerability with CsA-PG. In addition, CsA-PG necessitated incremental titration from 100 mg to 300 mg per inhalation to achieve the target dose; no titration was needed with L-CsA. Reported symptoms were (L-CsA vs CsA-PG): pharyngeal soreness 1% vs. 43%; cough 22% vs. 36%; dyspnea 7% vs. 25%; wheezing 1% vs. 7%; discontinuation due to symptoms caused by aerosol administration 0% vs. 7%. Adherence to investigational therapy (L-CsA vs CsA-PG) was 80% vs 60%. Conclusion L-CsA administered via an L-CsA specific PARI investigational eFlowr nebulizer improved tolerability and adherence compared to CsA-PG, another investigational aerosolized cyclosporine. L-CsA uses lower total dose exposure to achieve constant levels of drug in the airway.

Studies on application of annatto (Bixa orellena L.) dye formulations in dairy products.

Annatto is often used to add color to dairy products such as butter, cheese, or puddings. In India usage of annatto is restricted to butter and cheese, however there are no tailor made formulations available to obtain standardized colour shades for the products. Hence a study was initiated to develop the appropriate annatto dye formulations and level of application in few dairy products (butter, cheese, paneer, biscuit cream, icing cream). Dye extracted from annatto seeds was used for the preparation of water soluble potassium carbonate formulation (nor-bixin, 11.24%), oil soluble formulation (1.35% bixin) and an oil/water soluble propylene glycol formulation (PG formulation, 1.31% bixin). Lovibond tintometer colour units of the commercial butter, cheese and biscuit cream samples were measured for standardizing the colour concentration in the experimental products. The present study evaluates the application and stability of these formulations in butter, cheese, paneer, biscuit cream, icing cream. The products were evaluated for stability of colour and bixin during storage period. The oil/water soluble propylene glycol formulation was found to be tailor-made for all the dairy products studied though the standardized levels varied between 3.75 and 5.0mg/kg for butter, 3.75mg/kg for cheese, 5.0-400mg/kg for biscuit cream, 12.25 and 25mg/kg for paneer, 5.0-500mg/kg for icing cream. Increasing concentration in the range of 30-500mg/kg yielded products with light cream to orange shades, useful for decorating cakes. The average recovery of bixin from the products immediately after processing was 90-98%. Significant changes (P ≤ 0.05) were noticed in the colour units and recovery of bixin in all the products during storage of 6months.

Practical aspects of etomidate use in the management of hypercortisolaemia

We appreciate the letter from of Dr Soh et al. regarding our review on the use of etomidate in the treatment of Cushing's syndrome. We note that in their experience, our recommended dose regimen of 2.5 mg/h or thereabouts appears to be a safe and effective starting dose in most patients, and we note the utility and ease of use of the lipid formulation and its relative freedom from side effects compared with the more commonly used propylene glycol formulation; these are very helpful comments. Their experience in treating a further four patients is indeed further evidence of the usefulness of this agent.

Investigation of microemulsion microstructures and their relationship to transdermal permeation of model drugs: Ketoprofen, lidocaine, and caffeine

In this study, microemulsion microstructures, key formulation variables, and their relationship to drug transdermal permeation enhancement were investigated. A microemulsion system with high water soluble capacity was developed, using isopropyl myristate, Labrasol, and Cremophor EL as oil, surfactant, and co-surfactant, respectively. The microstructures of the microemulsions were characterized by a combination of techniques including electrical conductivity measurement (EC), differential scanning calorimetry (DSC), electro-analytical cyclic voltammetry (CV), dynamic light scattering (DLS). Three microemulsion formulations with the model drugs at water contents of 20%, 40%, and 70% representing the microstructures of W/O, Bi-continuous, and O/W were prepared along the water dilution line of oil to surfactant ratio of 1/9. Skin permeation of hydrophobic and hydrophilic model drugs, ketoprofen, lidocaine, and caffeine in the microemulsion formulations was studied using Franz-cells and dermatomed porcine skin. Permeation of all drugs from microemulsions was enhanced significantly compared with the control propylene glycol formulation. The drug permeation flux and the cumulative permeation amount after 24h increased with water content in the microemulsions, thus correlated to the formulation microstructures of W/O, Bi-continuous, and O/W. The permeation of lipophilic drugs ketoprofen and lidocaine increased with water content in a more pronounced manner, which seemed to follow an exponential growth trend, while the permeation of hydrophilic drug caffeine appeared to increase linearly. Additionally, at the same water content, increasing oil content led to higher ketoprofen permeation.

Improving the topical delivery of zinc phthalocyanine using oleic acid as a penetration enhancer: in vitro permeation and retention

Topical photodynamic therapy with zinc phthalocyanine (ZnPc), second-generation photosensitizer, can be an alternative method for the treatment of skin cancer. However, ZnPc has poor penetration in the skin. This study was aimed at investigating whether the presence of oleic acid (chemical enhancer) in propylene glycol can improve the topical delivery of ZnPc. The topical (to the skin) and transdermal (across the skin) delivery of ZnPc were evaluated in vitro using suine ear skin mounted in Franz diffusion cell. Photosensitizer was quantified by fluorescence emission, which is a sensitive and selective method. At 5 and 10%, oleic acid increased the topical and transdermal delivery significantly. When the concentration of oleic acid was further increased (20–60% w/w), the topical delivery of ZnPc was still elevated, but its transdermal delivery was substantially reduced. It was concluded that oleic acid (in propylene glycol formulations) can promote the topical delivery of ZnPc, with reduced transdermal delivery. This approach can be effective for the treatment of skin cancer by topical photodynamic therapy.

Oxybutynin permeation in skin: The influence of drug and solvent activity

The influence of degree of saturation (DS) of oxybutynin on permeation from octyl salicylate (OSAL) or propylene glycol (PG) vehicles was investigated, in vitro, in human skin. The permeation of OSAL and PG was also evaluated and the quantity of drug and solvent in the skin at the end of the diffusion study was measured. For OSAL the permeation of oxybutynin increased linearly with DS of drug for both 25 and 50% OSAL formulations. However, no differences were seen in oxybutynin permeation for formulations with the same DS but with different OSAL amounts, although the drug permeation was always slightly higher for 50% OSAL formulations. There was a decrease in the amount of OSAL extracted from skin with drug concentration (up to 5 DS). There was also a good correlation between the DS calculated from the amount of oxybutynin and OSAL extracted from the skin, and the actual DS of the formulation. In contrast oxbutynin DS did not affect PG permeation and there were no significant differences in oxybutynin permeation for the formulations with different DS. The lack of permeation enhancement for PG formulations appears to be related to PG depletion from the skin. The findings emphasise the importance of maintaining the drug in solution in order to achieve effective permeation from dermal and transdermal formulations.

The effect of drug concentration on solvent activity in silicone membranes

The effects of supersaturated formulations on drug permeation through artificial and biological membranes have been reported by a number of research groups. However, little information is known about solvent permeation from these supersaturated formulations, and in particular the effect of high drug concentrations and degree of saturation (DS) on solvent activity. The aim of this study was to determine the effect of the DS of a model drug, oxybutynin, on solvent and drug permeation. Supersaturated residues of oxybutynin in propylene glycol (PG) or (octyl salicylate) OSAL were prepared by the solvent evaporation method. In both formulations a high percentage (25%, v/v) of solvent was used in order to avoid solvent depletion. Permeation of PG and OSAL through silicone was monitored by GC and HPLC, respectively. All OSAL formulations permeated to a higher extent than PG formulations. A decrease in OSAL permeation with 5 DS formulations was observed in comparison with 1 DS or 2 DS formulations, indicating a decrease in solvent activity with drug concentration. In addition, the drug transport from the 5 DS formulation of OSAL was higher than the 1 and 2 DS formulations but lower than predicted. Based on both solvent and drug permeation, this suggests that the low drug permeation observed with 5 DS resulted from a decrease in solvent thermodynamic activity rather than a decrease in solute activity as a result of drug crystallisation. Using PG formulations, the PG permeation remained unaffected with the DS of the formulation, up to 5 DS.

Nontoxic Antifreeze for Insect Traps

Propylene glycol in water is a safe and effective alternative to ethylene glycol as a capture liquid in insect traps (pitfalls, flight intercepts, pan traps). Propylene glycol formulations are readily available because it is the primary (95%) ingredient in certain automotive antifreeze formulations. However, an even safer and less expensive alternative is the USP food grade RV antifreeze used for winterizing drinking water systems. The automotive formulations contain additives (about 5%) that contribute to the cost and involve safety, environmental, and waste disposal issues. Using bacterial inhibition as an indicator, the preservational attributes of the automotive and RV antifreeze were found to be comparable in laboratory tests. Entomologists are urged to use nontoxic antifreeze in their trapping programs.

Doxorubicin skin penetration from monoolein-containing propylene glycol formulations

Topical chemotherapy with the antineoplastic doxorubicin (DXR) could be an alternative to treat skin cancer, however its poor skin penetration often limits the efficacy of topical formulations. The aim of this work was to study the effect of monoolein (MO), a penetration enhancer, on the in vitro skin permeation and retention of DXR. DXR was incorporated in a propylene glycol preparation containing 0–20% of MO. DXR release rate and topical delivery were evaluated in vitro using acetate cellulose membrane and porcine skin, respectively, mounted in a Franz diffusion cell. At 5%, MO did not significantly change DXR release rate, but MO concentrations larger than 10% decreased almost twice its release. In vitro skin penetration studies showed that the presence of MO in the propylene glycol formulations markedly increased DXR presence in the stratum corneum (SC). At 5%, MO significantly increased the amount of DXR in the SC already in the first hours, attained a maximum in 6 h. Comparing propylene glycol formulations containing more than 10% MO with that containing 5%, the former took the double of the time (12 h) to reach the same amount of DXR in the skin, result that is in agreement with in vitro release studies. Interesting, despite the fact that MO significantly increased the amount of DXR in the SC, drug transdermal delivery did not change. These findings suggest a cutaneous delivery of DXR that is an important condition for topical treatment of skin tumors. Further in vivo experiments can show DXR delivery to deeper skin layers.

Stability and characterization of perphenazine aerosols generated using the capillary aerosol generator

Perphenazine (a potent antiemetic) was aerosolized using capillary aerosol generator to generate respirable condensation aerosols from drug in propylene glycol (PG) solutions, by pumping the liquids through a heated capillary tube. The study characterized the stability of perphenazine during and following aerosol generation. The stability-indicating HPLC method (C-8 column with a mobile phase of 52% 0.01 M pH 3.0 acetate buffer + 48% acetonitrile) also enabled the study of perphenazine stability in solution under acidic, basic, oxidizing and photolysing conditions. An LC–MS (ESI+) method was used to characterize the degradation products. Perphenazine was found to be stable in acidic and basic conditions, while perphenazine sulfoxide was the major product formed in dilute peroxide solutions. Two photo-degradation products were formed in PG that were tentatively identified by LC–MS; one of these was synthesized and confirmed to be 2-[4-(3-phenothiazin-10-yl-propyl)-piperazino]-ethanol. Both photolysis products showed that aromatic dechlorination had occurred and one appeared to also result from interaction with the solvent. Within an aerosolization energy window of 84–95 J, fine particle aerosols were generated from perphenazine PG formulations with no significant degradation. Small amounts of degradation products were produced in all samples during aerosolization at elevated (non-optimal) energies. These were largely consistent with those seen to result from oxidation and photolysis in solution, showing that oxidation and dehalogenation appeared to be the main degradation pathways followed when the CAG system was overheated.

Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer

Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5–70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20–70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery.

Solvent for etomidate may cause pain and adverse effects

We tested the hypothesis that the solvent for etomidate was a factor in the incidence of pain and other side effects after injection, and that these were associated with histamine release. Nine of 10 volunteers who received etomidate in a propylene glycol formulation reported moderate to severe pain on injection; only one of 10 subjects who received a lipid emulsion formulation reported mild pain (P < 0.05). The incidence of venous sequelae in the injected vein over the next 8 days was 50% in the propylene glycol group and 0% in the lipid emulsion group (P < 0.05). In one volunteer in the propylene group, there was a 13-fold increase in histamine concentrations and in one subject a four-fold increase. In the lipid emulsion group, no volunteer had an increase in histamine concentrations > 1 ng ml-1. We conclude that etomidate formulated in propylene glycol may cause direct injury to vascular endothelium resulting in pain and venous sequelae, whereas etomidate in lipid emulsion does not. There was no relationship between pain or venous sequelae and histamine release.

Haemolysis after etomidate: comparison of propylene glycol and lipid formulations

We sought to determine if the solvent in the formulation of etomidate is responsible for haemolysis in patients. In a randomized, prospective, double-blind study of 49 patients undergoing otolaryngological surgery, patients received etomidate dissolved in propylene glycol or in lipid emulsion. Concentrations of free haemoglobin and haptoglobin were measured before and for up to 360 min after injection of etomidate. Free haemoglobin concentrations increased by 216.8 mg litre-1 in patients who received the propylene glycol formulation and by 11.8 mg litre-1 in the lipid emulsion group (P < or = 0.0004). Correspondingly, reductions in haptoglobin concentrations were significantly greater in the propylene glycol group (P < or = 0.002). We conclude that with respect to haemolysis, lipid emulsion is superior to propylene glycol as a solvent for etomidate.

Differences in penetration-enhancing effect of Azone through excised rabbit, rat, hairless mouse, guinea pig and human skins

The transdermal delivery of dihydroergotamine (DHE), from propylene glycol formulations with and without 6.0% laurocapram (Azone), and the penetration enhancing effect of Azone were evaluated in vitro on excised rabbit, rat, hairless mouse, guinea pig and human skins utilizing improved Franz diffusion cells. The steady-state flux of DHE from the propylene glycol formulation without Azone were 0.045, 0.270, 0.395, 0.128 and 10.035 μg/cm 2 per h across excised human, rat, guinea pig, rabbit and hairless mouse, respectively. Under the influence of the enhancer, Azone increased DHE penetration through excised skin of the various species used in this study in the following order: rabbit skin > human skin > rat skin > guinea pig skin > hairless mouse skin. The maximum enhancement factor of Azone (251.47) was obtained across rabbit skin and the minimum enhancing effect (14.44) was observed in the case of hairless mouse skin. The enhancement factor of Azone across human skin was 54.56. These results show that animal skins are poor models for human skin under the conditions used. The lag time of DHE, from the propylene glycol formulation containing 6.0% Azone, through human skin was longer than the lag times across all other skin species tested in this investigation.

Evaluation of a noninvasive method for monitoring percutaneous absorption of lidocaine in vivo.

The pharmacodynamic measurement of in vivo skin penetration of lidocaine was explored with an instrument used in dentistry to determine tooth pulp vitality. The instrument delivers a low-current, pulsatile electrical waveform of increasing intensity with time. The readings, which are reproducible, are in arbitrary units on a scale of 0-80. Testing of naive sites showed variation as a function of location, even over relatively small distances. The response at a marked site over a 12-hr period generally was consistent in five subjects. Following intradermal administration of 1 or 2% lidocaine hydrochloride injection in one subject, the instrument reached its maximum value within 2 min. This was followed by a sustained plateau and then a gradual falloff of the effect. Topical formulations containing 5% lidocaine base and corresponding blank formulations were applied under occlusion within Hilltop chambers to intact skin on the forearms of human volunteers for 3 hr. While the response to a 40% propylene glycol formulation was not significantly different from the corresponding control, a cream exhibited slow development of profound anesthesia that lasted for several hours following chamber removal.

The lateral spread of clobetasol 17-propionate in the stratum corneum in vivo.

Radiolabelled clobetasol 17-propionate in two different bases, propylene glycol (PG) and di-n-butyl adipate (BA), was applied to the backs of 10 normal male volunteers, and the application sites protected. After 8 h samples of stratum corneum (SC) were taken from the application site and an adjacent site, and the level of steroid measured. At the application site there were higher concentrations of the PG formulation at the deeper levels of the SC. At the adjacent sites there were higher concentrations of the BA formulation at the superficial levels. The mean radioactivity at the adjacent sites expressed as a percentage of that at the corresponding application sites (+/- SEM) was 7.8 +/- 5.3% for the BA formulation and 3.0 +/- 2.9% for the PG, (P = 0.0002). Total percentage of the applied dose in the skin adjacent to the application site was 11.7 +/- 6.3% for the BA formulation and 5.3 +/- 5.7% for the PG (P less than 0.0002). Clobetasol 17-propionate, therefore, moves laterally to a greater extent in BA than in PG.

VENOUS SEQUENCE FOLLOWING ETOMIDATE

Five hundred patients receiving one of three different formulations of etomidate were observed on the 2nd and 3rd days after operation for possible venous sequelae. The total frequency of sequelae was 8% or more, the greatest being with the propylene glycol formulation (23%). Formulation of the drug and total dose employed were the most important factors influencing venous sequelae, which were not related to pain on injection.

EFFECT OF PREANAESTHETIC MEDICATION ON ETOMIDATE

The effects of diazepam and pethidine, when given as preanaesthetic medication, on the induction of anaesthesia and the postanaesthetic sequelae following etomidate were studied in women undergoing minor gynaecological procedures. Pain on injection was present in all the groups. However, the frequency was significantly less with the polyethylene glycol and propylene glycol formulations of the drug compared with the aqueous solution. A fast injection and pethidine premedication decreased the frequency also. The high frequency of excitatory phenomena in unpremedicated patients was decreased significantly by premedication with diazepam and pethidine, especially the latter. Respiratory and cardiovascular effects of the drug were not major problems. The frequency of emetic sequelae was high. Recovery was rapid even in the groups receiving sedative premedication.