Thórdís Kristmundsdóttir

Release of diltiazem from Eudragit microparticles prepared by spray-drying

Abstract Microparticles containing diltiazem hydrochloride were prepared by the spray-drying technique using acrylatemethacrylate copolymers, Eudragit RS and Eudragit RL, as coating materials. The choice of solvent used during spray-drying determined the structure of the resultant microparticles. Spray-drying using dichloromethane as the solvent resulted in microspheres where the drug was distributed in the coating polymer matrix, whereas using toluene gave microcapsules with the drug coated by the polymer. The particle size distribution for both microspheres and microcapsules was narrow, with mean particle size below 10 μm. DTA-analysis showed that the drug was amorphous in the microspheres but crystalline in the microcapsules. The release pattern of diltiazem hydrochloride was affected by microparticle structure, whether the structure was matrix (microspheres) or reservoir (microcapsules). The results indicate that spray-drying is a method that can be used to prepare microparticles from the Eudragit acrylic resins RL and RS with a narrow particle size distribution. It is concluded that drug release rate can be controlled by choice of polymer type and production conditions during spray-drying.

Solubilization of the lichen metabolite (+)-usnic acid for testing in tissue culture.

The pharmacological testing of natural products can often be hampered by the poor solubility of such compounds in non‐toxic solvents. There is thus a need for a suitable agent for solubilization of natural substances to allow testing on a variety of cell lines in‐vitro. Such an agent should ideally have no direct effects on any of the commonly used cell lines from a variety of tissues and mammalian species to allow proper comparison. In this study, the lichen metabolite (+)‐usnic acid, a dibenzofuran derivative, was used as a prototype for an insoluble natural product with the aim of finding a solvent that was both capable of solubilizing usnic acid and was free of direct activity against a test cell line. Solubilization was measured at different pH values in various concentrations of co‐solvents (glycofurol 75, propylene glycol, polyethylene glycol 400), surfactants (polysorbate 20 and Cremophor RH40), and the complexing agent 2‐hydroxypropyl‐β‐cyclodextrin. The solubility achieved in a 20% aqueous solution was 0.11 mg mL−1 for propylene glycol, 0.19 for PEG 400, 0.27 for glycofurol 75, 0.57 for Cremophor RH40, 0.68 for 2‐hydroxypropyl‐β‐cyclodextrin and 0.84 for polysorbate 20. The direct effects of the various solvent systems were tested on the human leukaemia cell line K‐562 in a standard proliferation assay. Most of the solvents proved toxic with the exception of propylene glycol, PEG 400 and 2‐hydroxypropyl‐β‐cyclodextrin. Anti‐proliferative activity of usnic acid could be demonstrated with an ED50 (amount of substance required to reduce thymidine uptake to 50% of uptake by untreated control culture) of 4.7μg mL−1 using PEG 400 and 2‐hydroxypropyl‐β‐cyclodextrin but only the latter gave satisfactory solubility. 2‐Hydroxypropyl‐β‐cyclodextrin was thus identified as a solubilizing agent that fulfilled both set criteria of solubility and lack of toxicity against the test cells.

Hydrogels containing monocaprin prevent intravaginal and intracutaneous infections with HSV-2 in mice: Impact on the search for vaginal microbicides

Hydrogel formulations containing the 1‐monoglyceride of capric acid (monocaprin) possess potent in vitro microbicidal activity against HIV and HSV, Chlamydia trachomatis and Neisseria gonorrhoeae. These formulations were studied to determine whether they prevent intracutaneous and intravaginal infections of mice with HSV‐2, a virus that is in vitro as sensitive to the virucidal action of the compound as is HIV. In mice intravaginal infection with HSV‐2 and the associated mortality was prevented completely when the infection was carried out in the presence of a 20 mM monocaprin containing gel formulation. Similarly, virtually complete protection of lesion development and associated mortality was observed when mice were infected intracutaneously with HSV‐2 in the presence of gels containing 10 or 20 mM monocaprin. No irritation or toxicity was observed following application of the gel to the skin or the vaginal mucosa. Hydrogel formulations of monocaprin could thus be pursued as vaginal microbicides for the prevention of sexual transmission of HSV, HIV and other infectious pathogens. J. Med. Virol. 61:107–110, 2000.

Potentiation of anticancer effects of microencapsulated carboplatin by hydroxypropyl α-cyclodextrin

Abstract Cyclodextrins are cyclic oligosaccharides that can change physicochemical properties of drugs by forming inclusion complexes with them. These changes may enhance the therapeutic potential of drugs by diminishing their decomposition before they enter tissues and by altering how they enter tissue. Carboplatin is an anticancer drug that is active against brain tumors and has recently been tested as a potential agent for interstitial chemotherapy. To test whether complex formulation with cyclodextrins would improve interstitial treatment with carboplatin, we studied the efficacy of carboplatin-cyclodextrin complexes, free and encapsulated, in an experimental rat glioma model. Carboplatin hydroxypropyl α-cyclodextrin complexes were incorporated into ethylcellulose microcapsules at a 2.2% w/w loading. We found that carboplatin was released from these microcapsules in a sustained manner for at least 110 days in vitro, that the rate was faster than that of encapsulated carboplatin alone, and that hydroxypropyl α-cyclodextrin protected the carboplatin from degradation. Further, the complex was more effective than carboplatin alone when tested on monolayers of F98 glioma cells. For testing the efficacy of the carboplatin-hydroxypropyl cyclodextrin complex in the rat glioma model, 56 Fischer rats were injected in the left hemisphere with F98 glioma cells. Five days later the rats were randomly divided into seven groups. Median survival of the first control group receiving no treatment was 20 days. The second group receiving an intratumoral injection of carboplatin had a median survival of 1 day, indicating severe cytotoxicity. The third group receiving systemic carboplatin had a median survival of 34 days. Median survival of the fourth group which received empty microcapsules was 24 days. The fifth group, treated with microcapsules loaded with hydroxypropyl α-cyclodextrin alone, showed a median survival of 20 days. The sixth group, treated with microcapsules loaded with carboplatin alone, showed a median survival of 34 days. The seventh group, treated with microcapsules loaded with carboplatin-hydroxypropyl α-cyclodextrin complex, showed a median survival of 51 days. This experiment demonstrated that the microencapsulated carboplatin-hydroxypropyl α-cyclodextrin complex is more effective than the nonencapsulated carboplatin. This study also shows that interstitial delivery of carboplatin-hydroxypropyl cyclodextrin complexes from a microencapsulated formulation is effective against experimental brain tumors.

Aqueous hydrocortisone mouthwash solution: clinical evaluation

Patients often experience difficulties in applying topical steroids in orabase to the oral mucosa, particularly when large areas need to be covered. An aqueous hydrocortisone mouthwash solution has been developed, one that was anticipated to be more acceptable to patients. The solution contains hydrocortisone (0.3% w/v) in a 4.5% (w/v) 2-hydroxypropyl-beta-cyclodextrin solution. Hydroxypropylmethylcellulose (0.5% w/v) was used to increase the viscosity of the solution and to promote the hydrocortisonecyclodextrin complex. One hundred and two patients with aphthous ulceration, lichen planus, and other mucosal conditions used the mouthwash in an open clinical efficacy study. Most patients reported some or considerable improvement following a 2-week course of treatment with the mouthwash: 26 of 33 (78.8%) patients with aphthous ulceration were much better, as were 26 of 54 (48.1%) patients with lichen planus and 5 of 16 (31.3%) patients with other mucosal lesions. No serious side effects were reported. Aqueous mouthwash solutions offer a potential vehicle for topical steroid therapy of oral mucosal lesions.

Virucidal activities of medium‐ and long‐chain fatty alcohols, fatty acids and monoglycerides against herpes simplex virus types 1 and 2: comparison at different pH levels

Previous studies have shown that certain lipids and fatty alcohols have microbicidal activities against a number of pathogens. In this study, virucidal activities of fatty alcohols and lipids were tested against HSV types 1 and 2 at various concentrations, times, and pH levels. The aim was first, to determine which compounds are most virucidal against HSV and could possibly be used as active ingredients in topical drug formulations and second, to attempt to throw light on the mode of action of virucidal lipids. Good agreement was found between the activities for HSV‐1 and HSV‐2. The activity of a compound depends on the concentration and time of contact and most of the compounds are more active at pH 4.2 than at pH 7. This information may be helpful in the formulation of pharmaceutical dosage forms for treatment of herpes lesions in skin and mucosa. The difference between the polar groups of alcohols and fatty acids, i.e. hydroxyl group versus carboxyl group, and the corresponding difference in their hydrophile‐lipophile balance (HLB) may explain their different virucidal activities against HSV. However, in most cases HLB numbers cannot explain the different virucidal activities of fatty alcohols and lipids, particularly not their increased activity at low pH. It is more likely that the acidic environment makes HSV more sensitive, possibly by ionic changes in the envelope proteins.

Virucidal activities of medium- and long-chain fatty alcohols and lipids against respiratory syncytial virus and parainfluenza virus type 2: comparison at different pH levels

SummaryRecent studies have shown that some lipids and fatty alcohols have microbicidal activities against a broad variety of pathogens. In this study, virucidal activities of fatty acids, monoglycerides and fatty alcohols were tested against respiratory syncytial virus (RSV) and human parainfluenza virus type 2 (HPIV2) at different concentrations, times and pH levels. The most active compounds were mixed with milk products and fruit juices and the mixtures tested for virucidal effects. The aim was to determine which compounds are the most active against these respiratory viruses and could possibly be used in pharmaceutical formulations or as additives to milk products or juice. Several compounds caused a significant inactivation of virus, and there was generally a good agreement between the activities against RSV and parainfluenza virus. By changing the pH from 7 to 4.2, the virucidal activities of some of the compounds were greatly increased, i.e., they inactivated virus in a shorter time and at lower concentrations. The most active compound tested was 1-monoglyceride of capric acid, monocaprin, which also showed activity against influenza A virus and significant virucidal activities after addition to milk products and fruit juices, even at a concentration as low as 0.06–0.12%. The significant virucidal activities of fatty alcohols and lipids on RSV and parainfluenza virus demonstrated in this in vitro study raise the question of the feasibility of using such compounds as ingredients in pharmaceutical dosage forms against respiratory infections caused by these viruses, and possibly other paramyxo- and myxoviruses.

Clinical assessment of the effect of a matrix metalloproteinase inhibitor on aphthous ulcers

Objective. Aphthous ulceration is a common form of recurrent ulceration of the oral mucosa. Numerous treatments have been tried as a means of relieving pain, disinfecting the ulcer base, and reducing inflammation, but with limited success. Tetracycline and its derivatives have been shown to be inhibitors of matrix metalloproteinases (MMPs), which are part of the inflammatory response and contribute to the breakdown of tissue in the ulcer. Of the commercially available tetracyclines, doxycycline has shown the best inhibition of the MMPs. The aim of this study was to test clinically whether the inhibitory effect of a low-dose doxycycline in a hydrogel on MMPs would speed the recovery of oral ulceration. Material and Methods. Forty-nine patients participated in a randomized, double-blind, placebo-controlled trial. Results. Sixty-eight percent of ulcers had healed by the third day of treatment with the doxycycline gel, whereas only 25% of the patients receiving the placebo reported healing of their ulcers within 3 days. Patients treated with the docycline gel recounted faster reduction in pain during the treatment period than the placebo group did. Conclusions. Incorporation of low-dose doxycycline in a muco-adhesive gel has been demonstrated to have potential in the treatment of recurrent oral ulceration. It is concluded that MMP enzymes can be inhibited by low doses of doxycycline below levels likely to disrupt the oral flora.

Formulation and clinical evaluation of a hydrocortisone solution for the treatment of oral disease

The purpose of this study was the formulation and clinical evaluation of a steroid solution for the treatment of oral disease. The steroid used for this work was hydrocortisone and its solubility was increased by complex formation with 2-hydroxypropyl-β-cyclodextrin. In a clinical efficacy study of the hydrocortisone solution in 50 patients, there were no reports of ill effects and no side effects such as erythema or superinfection were noticed. Of those treated, 78% showed improvement, with 48% showing considerable clinical improvement. The preliminary clinical observations show that this hydrocortisone solution was easy to use, had a clinical efficacy that compares well with much more potent preparations and thus should help to minimise the prevalence of harmful side effects of the treatment of these distressing conditions.

A study of the clinical activity of a gel combining monocaprin and doxycycline: a novel treatment for herpes labialis

BACKGROUNDnCurrent treatment of herpes labialis is usually with topical antiviral drugs and early drug administration is required for effectiveness. Monocaprin, a 1-monoglyceride of capric acid, has high microbicidal activity in vitro and efficiently inactivates herpes simplex virus. Tetracyclines are inhibitors of matrix metalloproteinases that are part of the inflammatory response and contribute to the breakdown of tissue in ulcers. The study objective was to investigate the antiviral and wound-healing effect of a hydrogel containing either monocaprin or a combination of monocaprin and a low dose of doxycycline in vivo against herpes labialis.nnnMETHODSnSubjects were divided into two groups: (i) with prodromal symptoms of herpes labialis; (ii) with a vesicle. Both groups applied the hydrogel five times a day for five days. Test formulations were: (i) hydrogel containing monocaprin and doxycycline (MCD), (ii) hydrogel containing only monocaprin and (iii) placebo hydrogel. Formulations were distributed randomly to subjects within each group. Subjects recorded treatment results in a 6-day diary and a 7-day follow-up diary.nnnRESULTSnFor the MCD group the mean time to healing was 5.5 days (prodromal) and 5.3 days (vesicles/ulceration) or significantly shorter than for the placebo groups (7.25 and 7.5 days respectively; P < 0.05). Pain relief was significantly more with MCD (combining both the prodromal and vesicle groups) than with the monocaprin and placebo groups (P = 0.0114).nnnCONCLUSIONnCombining monocaprin with low-dose doxycycline offers an effective treatment for herpes labialiss, significantly reducing time to healing and pain compared with the placebo and monocaprin alone.