Topical Cream Formulations Research Articles

Pharmacological evaluation of ethanolic extract of Daucus carota Linn root formulated cream on wound healing using excision and incision wound model

ObjectiveDaucus carota L. (Carrot) (Apiaceae) is used in the traditional medicine for the treatment of variety of ailments. The aim of present investigation was to formulate and evaluate wound healing activity of ethanolic extract of Daucus carota L. root on excision wound model and incision wound model. MethodsThe soft paraffin based cream containing 1%, 2% and 4% w/w of ethanolic extract of Daucus carota L. (EEDC) root was formulated and evaluated for pharmaceutical parameters such as rheological properties, pH, skin irritation and external characters. Excision wounds sized 300 mm2 and 2 mm depth were used for the study of rate of contraction of wound and epithelization at different time intervals. Incision wounds six centimeter long and two linear-paravertebral incisions were used for the study of tensile strength, total protein and hydroxyproline content measured on 10th day old incision wound. ResultsEthanolic extract of Daucus carota L. root cream formulation when applied topically did not show any sign and symptoms of skin irritation. Animals treated with topical EEDC cream formulation (1%, 2% and 4% w/w) showed significance decrease in wound area, epithelization period and scar width whereas rate of wound contraction significantly increased (P <0.01, P <0.001 and P <0.001 resp.) as compared to control group animals in excision wound model. In incision wound model there was significant increase (P <0.01 and P <0.001) in tensile strength, hydroxyproline content and protein content of animals treated with topical EEDC cream formulation (2% and 4% w/w, respectively). ConclusionsWound-healing property of ethanolic extract of Daucus carota L. root may be attributed to the various phytoconstituents like flavonoids and phenolic derivatives present in the root and the quicker process of wound healing could be a function of either its antioxidant or antimicrobial potential. The present findings provide scientific evidence to the ethanomedicinal properties of Daucus carota in wounds healing activity.

Ivermectin Acts as a Posteclosion Nymphicide by Reducing Blood Feeding of Human Head Lice (Anoplura: Pediculidae) That Hatched From Treated Eggs

The 0.5% ivermectin topical cream formulation was not directly ovicidal to treated eggs of head lice, as hatchability was not decreased. Nevertheless, the percent of hatched lice from treated eggs that took a blood meal significantly decreased (80-95%) compared with lice that hatched from untreated eggs and all treated lice died within 48 h of hatching, including those that fed. Dilutions of ivermectin formulation of 0.15 and 0.2 microg/ml, which were topically applied to 0-8 d old eggs, were not lethal to lice at 24 h posteclosion. However, 9 and 16% less lice fed when hatched from these treated eggs, respectively. Total [3H] inulin ingested by untreated first instars significantly increased over a 48 h feeding interval but was significantly less in instars that hatched from eggs receiving the 0.15 (36% less) and 0.2 (55% less) microg/ml ivermectin treatments compared with placebo. The reduced feeding that occurred after the 0.15 and 0.2 microg/ml ivermectin treatments occurred in the absence of mortality and suggests a unique mode of action of ivermectin on feeding that is separate from the mode of action of ivermectin leading to mortality. Failure of hatched instars to take a blood meal after egg treatments with formulated ivermectin is likely responsible for its action as a posteclosion nymphicide.

Photodegradation of (−)-epigallocatechin-3-gallate in topical cream formulations and its photostabilization

The aim of the study was to examine the photostability of the major catechin of green tea, (−)-epigallocatechin-3-gallate (EGCG), which possesses important antioxidant and skin photoprotective properties. In order to simulate realistic conditions of use of topical preparations, the photolysis studies were performed in model creams (oil-in-water emulsions) containing 1% (w/w) EGCG and exposed to a solar simulator at an irradiance corresponding to natural sunlight. The extent of photodegradation was measured by HPLC–UV and HPLC–ESI-MS. EGCG was found to decompose by 68.9 ± 2.3%, after 1 h irradiation. Addition of the coantioxidants, vitamin E or butylated hydroxytoluene to the emulsion formulation, significantly enhanced the photolability of the catechin, the EGCG loss reached 85.7 ± 1.3% and 80.5 ± 1.4%, respectively. On the other hand, inclusion of the UVB (290–320 nm) filter, ethylhexyl methoxycinnamate in the cream produced a small but significant reduction of EGCG photodegradation to 61.0 ± 2.9%, while the UVA (320–400 nm) filter, butyl methoxydibenzoylmethane was ineffective (EGCG degradation, 67.8 ± 1.5%). A more marked decrease in the light-induced decomposition of EGCG to 51.6 ± 2.7% was achieved, under the same conditions, using the water-soluble UVB filter, benzophenone-4 (BP-4). This effect was concentration dependent, maximal EGCG photostabilization (catechin loss, 29.4 ± 2.2%) was attained in the presence of 2.1% (w/w) BP-4. Therefore, BP-4 represents a useful additive to improve the light stability of EGCG in topical formulations for skin photoprotection.

Preformulation, formulation, and in vivo efficacy of topically applied Apomine

Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy. This research was focused on the development of a new delivery approach for chemoprevention of melanoma using topically delivered Apomine. This included evaluating the effect of several factors on the stability of Apomine in solution, utilizing these to develop a topical formulation, and conducting efficacy studies with the developed topical formulation in the TPras mouse model. Preformulation included the influence of pH, buffer species, ionic strength, and organic solvents on the stability of Apomine at four different temperatures. Apomine was determined to undergo apparent first-order degradation kinetics for all conditions evaluated. Apomine undergoes base-catalyzed degradation. Less than 15% degradation is observed after >200 days under acidic conditions. Long-term stability studies were performed on two different topical cream formulations and indicate that both formulations are chemically stable for over 1 year at both 4 and 23 °C. The efficacy of topically applied Apomine, from ethanol and developed 1% cream, was evaluated in vivo against the incidence of melanoma. Regardless of delivery vehicle Apomine treatment caused a significant reduction in tumor incidence. Ethyl alcohol application of Apomine resulted in a greater tumor incidence reduction when compared to the development cream formulation; however, this difference was not significant.

Evaluation of Adrenal Suppression of a Lipid Enhanced, Topical Emollient Cream Formulation of Hydrocortisone Butyrate 0.1% in Treating Children with Atopic Dermatitis

Corticosteroids are currently the first line of treatment for patients with atopic dermatitis. In the pediatric population however, the potential impact of adrenal suppression is always an important safety concern. Twenty boys and girls, 5-12 years of age, with normal adrenal function and a history of atopic dermatitis were maximally treated three times daily with a lipid-rich, moisturizing formulation of hydrocortisone butyrate 0.1% for up to 4 weeks. At the conclusion of the 4-week treatment period, cosyntropin injection stimulation testing showed no evidence of adrenal suppression. In addition, the therapy was noted to be highly efficacious, with a clinical success rate of 80% (Physician Global Score of (0) clear or (1) almost clear). No local side effects associated with prolonged use of topical corticosteroids were reported. In summary, this study supports the contention that this lipid-rich, moisturizing formulation of hydrocortisone butyrate 0.1% was a well-tolerated and beneficial treatment for atopic dermatitis, demonstrating no adrenal suppression in the pediatric population aged 5-12 years. The relevance of these findings for children below 5 years of age, because of difference in body mass/surface area ratios, remains to be determined.

Determination of neomycin sulfate and impurities using high-performance anion-exchange chromatography with integrated pulsed amperometric detection

Neomycin B is one of a class of aminoglycoside antibiotics that lack a good chromophore, and is therefore difficult to determine using reversed-phase HPLC with absorbance detection. This is especially true for determining the quantity of each impurity. We show that neomycin sulfate and its major impurities, including neamine (neomycin A), can be separated on a strong anion-exchange column using a weak potassium hydroxide eluent (2.40 mM) at a column temperature of 30 °C, and directly detected by integrated pulsed amperometric detection (IPAD). The resolution (United States Pharmacopeia (USP) definition) between neomycin B and the closest major impurity ranged from 6.56 and 7.45 over 10 days of consecutive analysis (7.24 ± 0.10, n = 836 injections). Due to the difficulty of producing weak hydroxide eluents of the required purity (i.e. carbonate-free), this method depends on automatic eluent generation to ensure method ruggedness. This method exhibited good long-term (10 days, 822 injections) retention time stability with a R.S.D. of 0.6%. Peak area R.S.D. (10 μM) was 1.3%. Method robustness was evaluated by intentionally varying the flow rate, eluent concentration, column temperature, and column. The spike recoveries of neomycin B from extractions of three different topical ointments and cream formulations ranged from 95 to 100%. The measured concentration of neomycin B in these formulations ranged from 119 to 154% of the label concentration. The R.S.D. for the measured concentration of one of the formulations tested over three separate days, n = 11 extracts, was 3.2%. Based on the results of these evaluations, we believe this method can be used for neomycin sulfate identity, assay, and purity.

Development of an HPLC method for the analysis of Apomine in a topical cream formulation

A stability indicating, reversed-phase high performance liquid chromatographic method was developed for the quantification of Apomine, tetraisopropyl 2-(3,5-di- tert-butyl-4-hydroxyphenyl)-ethyl-1, 1-bisphosphonate, in a topical cream formulation. Analysis of Apomine in the cream formulation was performed through a dilution of the cream base with tetrahydrofuran. This allowed the current method to bypass extraction and/or centrifugation for direct injection and analysis. Separation was achieved using an Alltima C 18 5 μm, 150 mm × 2.1 mm column and employed a gradient procedure, beginning with acetonitrile–water (65:35, v/v), at 0.6 mL/min for 9 min, followed by a rinse with isopropyl alcohol for 9 min. The complete gradient method has been optimized to separate Apomine from the nonpolar cream components, wash and equilibrate the column in a 30-min assay. This report demonstrates that this method is effective for quantification of Apomine in a cream formulation.

Dermal Delivery of Topically Applied Oligonucleotides via Follicular Transport in Mouse Skin

Antisense oligodeoxynucleotides formulated in cream preparations are being examined in the clinic as topical therapy for psoriasis. To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topically applied phosphorothioate antisense oligonucleotide targeted to intercellular adhesion molecule-1 recently was shown to modulate cytokine-inducible target gene expression in engrafted human skin. In this study, we examined the route of entry into mouse skin of fluorochrome-tagged or naked second-generation 2'-O-methoxyethyl-modified oligonucleotides that react specifically with an antibody, using topical cream-based formulations. In hairless mouse skin, immunohistochemical analysis and fluorescence microscopy were unable to detect the presence of oligonucleotide in the epidermis or dermis following topical application although immunostaining was associated with the stratum corneum and fluorescein isothiocyanate-labeled oligonucleotide was observed in hair follicles. Kinetic analysis of oligonucleotide topically applied to hair-clipped BALB/c mouse skin showed early follicular localization, diffusion of oligonucleotide from the mid-follicle, and subsequent dermal accumulation. Saline formulation resulted in oligonucleotide remaining within the hair follicle. These results suggest that oligonucleotide penetration in skin involves a follicular route and further, that topical oligonucleotide therapy may be particularly well suited for altering physiology within the hair follicle and related structures.

An HPLC method for quantitation of perillyl alcohol in a topical pharmaceutical cream formulation

A reverse phase high performance liquid chromatographic method for quantitation of perillyl alcohol in a topical cream pharmaceutical formulation was developed. Previously reported methods for analyzing drugs in lipid formulations are relatively complex and time consuming, with extraction, purification and derivatization involved. Through a simple dilution of the cream formulation in isopropyl alcohol, the present assay method enables the direct injection of the samples, on an Alltima C18 5 μ, 150 mm × 2.1 mm, narrow bore column (Alltech Associates, Deerfield, IL). The method includes an isocratic run with acetonitrile–water (40:60, v/v) at 0.35 mL/min for 12 min, followed by a gradient wash with isopropyl alcohol for 20 min, to ensure that all formulation excipients are eluted. Ultraviolet detection was performed at 210 nm with a retention time for perillyl alcohol of 7 min. The high sensitivity assay utilizes a small (5 μL) injection volume for the accurate and precise analysis of perillyl alcohol from a complex cream formulation.

The Potential of Raman Spectroscopy as a Process Analytical Technique During Formulations of Topical Gels and Emulsions

The primary objective of this study is to investigate the possibility of using Raman spectroscopy as a process analytical technique (PAT) for quality control during manufacturing of topical dosage forms. A fiber-optic Raman probe was used to monitor the formulation of pharmaceutical gel and emulsion in laboratory scale. Raman shifts of typical commercial raw materials used in topical dosage forms were measured to ascertain the potential of this technique for monitoring and analyzing topical products. Spectra of some well-characterized topical gels manufactured in our laboratory were also measured. Commercial raw materials were found to be Raman sensitive. Due to the difference in chemical composition, raw materials exhibit characteristic peaks that can be exploited to monitor formulation processes. Spectra taken during formulation of an emulsion using Carbopol Ultrez as thickener and Tefose as emulsifying agent show changes in Raman shifts immediately after major formulation steps. The findings from this work suggest that Raman spectroscopy can be a valuable process analytical technique for quality control of topical gel and cream formulations.

Development of a perillyl alcohol topical cream formulation

Perillyl alcohol (POH) is a relatively non-toxic agent that has been shown to be a promising anticancer monoterpene in preclinical models. Studies have indicated that topical application of POH may prove to be effective as a skin cancer chemoprevention therapy. The main aim of this study was to determine the influence of several factors on the stability of POH in solution and develop a topical formulation of POH. During preformulation, the influence of pH, temperature, ionic strength, and organic solvents, on the stability of POH was evaluated at four different temperatures: 4, 25, 37, and 48 °C. POH was found to degrade under acidic conditions with degradation following apparent first-order kinetics. A hydrophilic topical cream formulation of POH was developed and prepared for toxicology and clinical studies. A reverse phase gradient HPLC method was developed to quantitate POH in the complex formulation. Stability studies of the formulation and a placebo were performed and the formulation was found to be physically and chemically stable over a period of 1 year at 4 and 25 °C.

Determination of capsaicinoids in topical cream by liquid–liquid extraction and liquid chromatography

A reversed-phase liquid chromatography (LC) method has been developed, optimised and validated for the separation and quantitation of capsaicin (CP) and dihydrocapsaicin (DHCP) in a topical cream formulation. Sample preparation involves liquid–liquid extraction prior to LC analysis. The method uses a Hypersil C 18 BDS, 5 μm, 250×4.6 mm I.D. column maintained at 35 °C. The mobile phase comprises methanol, water, acetonitrile (ACN) and acetic acid (47:42:10:1, v/v/v/v) at a flow rate of 1.0 ml/min. Robustness was evaluated by performing a central composite face-centred design (CCF) experiment. The method shows good selectivity, linearity, sensitivity and repeatability. The conditions allow the separation and quantitation of CP and DHCP without interference from the other substances contained in the cream.

Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea

Background: The papules and pustules of rosacea can be effectively treated with topical metronidazole. The optimal concentrations of metronidazole and optimum frequencies of application are uncertain. Traditionally, twice-daily applications have been advised, based on the pharmacokinetic profile of metronidazole. Once-daily applications may be safer and less expensive, and they may enhance patient compliance. Objective: We compared the efficacy and safety of 2 commercially available topical metronidazole formulations (0.75% metronidazole cream formulation and 1.0% metronidazole cream formulation) when both were used in a once-daily regimen. Methods: A multicenter, randomized, investigator-blind, parallel group trial was conducted at 3 separate clinical sites located in 3 US cities. The study enrolled 72 rosacea patients with at least 8 to 50 inflammatory facial lesions (pustules and papules) and moderately severe facial erythema. Patients were randomly assigned to receive either 0.75% metronidazole cream or 1.0% metronidazole cream and instructed to apply the medication once daily for 12 weeks. Patients' lesions were evaluated at baseline and at weeks 3, 6, 9, and 12. Results: There were no significant differences between treatment groups for any of the efficacy parameters evaluated. The overall median percentage change in lesion count at end point for patients in the 0.75% metronidazole cream treatment group was −62% compared with −60% for the 1.0% metronidazole cream treatment group. The overall percentage change in erythema scores at endpoint for patients in the 0.75% metronidazole cream treatment group was −26% compared with −30% for patients in the 1.0% metronidazole cream treatment group. Regarding physician assessment of global severity, 57% of subjects (20/35) in the 0.75% metronidazole cream group compared with 37% of subjects (13/35) in the 1.0% metronidazole cream group were rated as having a clear to mild condition at end point. Both drugs were well tolerated; there was no significant difference in the number of drug-related adverse events between the two agents. Conclusion: This controlled trial demonstrates that both 0.75% metronidazole cream and 1.0% metronidazole cream, when used once daily, provide well-tolerated efficacy for moderate to severe rosacea. (J Am Acad Dermatol 2001;45:723-30.)

Submicron Emulsion Vehicle for Enhanced Transdermal Delivery of Steroidal and Nonsteroidal Antiinflammatory Drugs

Significant improvement is demonstrated for transdermal delivery of steroidal and nonsteroidal antiinflammatory drugs (NSAID), including betamethasone valerate and dipropionate, indomethacin, diclofenac, piroxicam, and naproxen, when formulated in a submicron Emulsion (SME) vehicle rather than in standard creams. SMEs comprise oil droplets, with mean size of ∼100nm (0.1 µm), dispersed in a continuous water phase. Hydrophobic drugs are incorporated into the oil phase of the SME, resulting in improved penetration and increased efficacy of the incorporated antiinflammatory drug. The performance of medicated topical SME was compared with that of regular topical cream formulations, as measured by the carrageenan‐induced paw edema rat model. Indomethacin in SME topical vehicle was 50% more active than in regular cream base, Diclofenac in SME proved to be 40% more active than Voltaren Emulgel. Improvement of steroidal antiinflammatory drugs action in topical SME cream was even more pronounced; that is, up to 3–4‐fold. Antiinflammatory drugs in SME also demonstrate noticeable systemic activity, but for regional edema treatment, local delivery is advantageous. The new SME delivery system was tested for primary irritation in humans in a 48‐h trial. Low irritancy and excellent human acceptance for SME placebo or diclofenac‐loaded SME cream make this novel transdermal/topical DDS attractive for further development.

Development and Validation of Method for Determination ofIn VitroRelease of Retinoic Acid from Creams

AbstractThe objective of this study was to develop and validate an in vitro test method that can be used as a tool for accessing batch-to-batch uniformity of finished topical products. The studies were performed by utilizing topical creams containing the 13-cis isomer of retinoic acid. Various physicochemical factors which may affect drug release from topical cream formulations were evaluated including drug concentration, internal phase droplet size distribution, viscosity and the composition of the emulsion internal and external phases. Utilizing a modified Franz diffusion cell with a cellulose membrane, the in vitro drug release profile from various cream formulations was establishedThe effect of varying the concentrations of various key ingredients by 30% does affect the viscosities and release rates compared to a standard formulation. However, there is no correlation between the viscosities and the release rates. No significant differences in pH and droplet size distribution were observed in these cre...

Temperature and pH dependence of fluocinolone acetonide degradation in a topical cream formulation.

We investigated the degradation of fluocinolone acetonide (FA) incorporated into an oil-in-water cream base. The study examined the influence of temperature (23 to 80 degrees C) and cream pH (pH 2.3 to 6) on FA degradation rates. FA degradation followed pseudo-first-order kinetics and adhered to the Arrhenius expression over the entire temperature range investigated. At all temperatures, the pH strongly influenced the observed degradation rate constant (kobs) values, with rate minima observed near pH 4. The FA log(degradation rate)-pH profiles were consistent with a reaction mechanism requiring drug hydrolysis catalyzed by hydroxide and hydrogen ions. Taking into account both the temperature and the pH dependence of FA degradation permits calculating kobs values from the following equation: kobs = exp[22.5 - (17,200/RT)] + exp[38.7 - (22,200/RT)] x [H+] + exp[49.5 - (21,100/RT)] x [OH-] where the three bracketed terms represent Arrhenius expressions for neutral, acid-catalyzed, and base-catalyzed hydrolysis reactions. FA degradation in the cream base parallels the degradation of a related steroid (triamcinolone acetonide) in an aqueous alcohol solution. The equivalence between FA and triamcinolone acetonide kinetics in the different reaction media suggests that in the cream base, FA degradation is limited to an aqueous phase largely unperturbed by the presence of nonaqueous constituents that comprise the cream formulation.

Automated high-performance liquid chromatographic column switching technique for the on-line clean-up and analysis of drugs in topical cream formulations

The automation of a high-performance liquid chromatographic column switching technique for the on-line clean-up and analysis of drug substances in topical cream formulations is described. A short reversed-phase precolumn used for primary sample clean-up was coupled to a reversed-phase analytical column. This allowed cream samples dissolved in methanol—tetrahydrofuran to be injected directly into the analysis system without prior laborious and time-consuming clean-up procedures. This application was successfully extended to the analysis of sulconazole nitrate, and a triple corticoid cream. The effects of precolumns on some chromatographic parameters were studied.

On-line HPLC method for clean-up and analysis of hydrocortisone and sulconazole nitrate in a cream

The application of a new on-line high-performance liquid Chromatographic method for the clean-up and analysis of drugs in semi-solid formulations was investigated. A short column of a chemically bonded stationary phase (10 μm octadecylsilane) mounted into the sample loop position of the high pressure injection valve was used as the primary clean-up step. The elution behavior of commonly used cream excipients on the loop column as a function of various combinations of water, methanol and THF was studied using a refractive index detector. Typically, samples of the cream were dissolved in methanol-THF and injected onto the loop column. The drug substances were eluted onto the analytical column with predetermined volumes of the mobile phase. The relatively non-polar cream excipients were retained on the loop column. At this time the injection valve was switched, isolating the loop column and the retained excipients were eluted off to waste with a strong solvent (methanol-THF). Loss of efficiency due to the insertion of the loop column was negligible. This technique was applied to the simultaneous analysis of a corticosteroid (hydrocortisone) and a hydrophobic amine (sulconazole nitrate) in a topical cream formulation.