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Pharmaceutics, Volume 6, Issue 3 (September 2014), Pages 354-542

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Research

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Open AccessArticle The Flux of Select NSAIDs through Silicone Membranes from Mineral Oil
Pharmaceutics 2014, 6(3), 354-365; doi:10.3390/pharmaceutics6030354
Received: 23 May 2014 / Revised: 16 June 2014 / Accepted: 23 June 2014 / Published: 2 July 2014
Cited by 1 | PDF Full-text (855 KB) | HTML Full-text | XML Full-text
Abstract
Here we report the experimental log maximum fluxes of n = 9 non-steroidal anti-inflammatory drugs (NSAID) through silicone membranes from the lipid mineral oil (experimental (Exp.) log JMPMO) and correlate those Exp. log JMPMO values with their experimental log [...] Read more.
Here we report the experimental log maximum fluxes of n = 9 non-steroidal anti-inflammatory drugs (NSAID) through silicone membranes from the lipid mineral oil (experimental (Exp.) log JMPMO) and correlate those Exp. log JMPMO values with their experimental log maximum fluxes through human skin in vivo from mineral oil (Exp. log JMHMO). The correlation was only fair (r2 = 0.647) for n = 9 but improved dramatically if Nabumetone was removed from the correlation (n = 8, r2 = 0.858). Non-linear regression of the n = 8 Exp. log JMPMO values as the dependent variable against their log solubilities in mineral oil (log SMO) and in pH 7.4 or 1.0 buffers (log S7.4 or S1.0, respectively), and their molecular weights as independent variables in the Roberts–Sloan (RS) equation gave a new set of coefficients for the independent variables in RS. Those coefficients have been used to calculate log JMPMO values which have been correlated with the Exp. log JMPMO values to give r2 = 0.911 if log S7.4 and r2 = 0.896 if log S1.0 were used as aqueous phases. Thus, silicone membranes appear to be good surrogates for predicting flux through human skin if the vehicle is a lipid such as mineral oil. Full article
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Open AccessArticle Release of Tenofovir from Carrageenan-Based Vaginal Suppositories
Pharmaceutics 2014, 6(3), 366-377; doi:10.3390/pharmaceutics6030366
Received: 15 April 2014 / Revised: 13 June 2014 / Accepted: 25 June 2014 / Published: 4 July 2014
Cited by 2 | PDF Full-text (845 KB) | HTML Full-text | XML Full-text
Abstract
Microbicides are an active area of research for HIV prevention, being developed as a woman-initiated method of prevention during unprotected coitus. Along with safety and efficacy, assessing and improving compliance is a major area of research in microbicide development. We have produced [...] Read more.
Microbicides are an active area of research for HIV prevention, being developed as a woman-initiated method of prevention during unprotected coitus. Along with safety and efficacy, assessing and improving compliance is a major area of research in microbicide development. We have produced microbicide prototypes in the form of semisoft vaginal suppositories prepared from carrageenan and conducted both qualitative and quantitative studies using these prototypes to determine the physical properties that drive acceptability and possibly adherence. In order to ensure that the suppositories function as effective drug delivery vehicles, we have conducted in vitro dissolution studies in water, vaginal simulant fluid (VSF) and semen simulant fluid (SSF) with suppositories loaded with the antiretroviral drug, tenofovir (TFV). TFV was released via diffusion and matrix erosion in water or by diffusion out of the matrix in VSF and SSF. Diffusion studies were conducted in two different volumes of VSF and SSF. The volume of VSF/SSF into which TFV diffused and the size of the suppositories determined the rate of diffusion from the suppositories. About 45%–50% of the encapsulated TFV diffused out of the suppositories within the first two hours, irrespective of suppository size, diffusion medium (VSF/SSF) and the volume of medium. Prior work indicates that a short waiting period between insertion and coitus is highly desired by women; present data suggest our microbicide prototypes have rapid initial release followed by a slow release curve over the first 24 h. Full article
(This article belongs to the Special Issue Dosage Forms and Delivery Systems for Vaginal Therapy)
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Open AccessArticle Improving Co-Amorphous Drug Formulations by the Addition of the Highly Water Soluble Amino Acid, Proline
Pharmaceutics 2014, 6(3), 416-435; doi:10.3390/pharmaceutics6030416
Received: 28 May 2014 / Revised: 23 June 2014 / Accepted: 1 July 2014 / Published: 14 July 2014
Cited by 11 | PDF Full-text (783 KB) | HTML Full-text | XML Full-text
Abstract
Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture [...] Read more.
Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 °C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP–TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP–ARG. In comparison to crystalline NAP, binary NAP–TRP and NAP–ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations. Full article
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Open AccessArticle Mixing Acid Salts and Layered Double Hydroxides in Nanoscale under Solid Condition
Pharmaceutics 2014, 6(3), 436-446; doi:10.3390/pharmaceutics6030436
Received: 6 June 2014 / Revised: 22 July 2014 / Accepted: 23 July 2014 / Published: 30 July 2014
Cited by 2 | PDF Full-text (2136 KB) | HTML Full-text | XML Full-text
Abstract
The immobilization of potassium sorbate, potassium aspartate and sorbic acid in layered double hydroxide under solid condition was examined. By simply mixing two solids, immobilization of sorbate and aspartate in the interlayer space of nitrate-type layered double hydroxide, so called intercalation reaction, [...] Read more.
The immobilization of potassium sorbate, potassium aspartate and sorbic acid in layered double hydroxide under solid condition was examined. By simply mixing two solids, immobilization of sorbate and aspartate in the interlayer space of nitrate-type layered double hydroxide, so called intercalation reaction, was achieved, and the uptakes, that is, the amount of immobilized salts and the interlayer distances of intercalation compounds were almost the same as those obtained in aqueous solution. However, no intercalation was achieved for sorbic acid. Although intercalation of sorbate and aspartate into chloride-type layered double hydroxide was possible, the uptakes for these intercalation compounds were lower than those obtained using nitrate-type layered double hydroxide. The intercalation under solid condition could be achieved to the same extent as for ion-exchange reaction in aqueous solution, and the reactivity was similar to that observed in aqueous solution. This method will enable the encapsulation of acidic drug in layered double hydroxide as nano level simply by mixing both solids. Full article
(This article belongs to the Special Issue Layered Double Hydroxide Used in Drug Delivery)
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Open AccessArticle Temperature Dependence of the Complexation Mechanism of Celecoxib and Hydroxyl-β-cyclodextrin in Aqueous Solution
Pharmaceutics 2014, 6(3), 467-480; doi:10.3390/pharmaceutics6030467
Received: 19 June 2014 / Revised: 23 July 2014 / Accepted: 31 July 2014 / Published: 13 August 2014
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Abstract
Hydroxypropyl-β-cyclodextrin (HP-β-CD) is commonly used as a complexation reagent to solubilize compounds with poor aqueous solubility to improve in vivo dosing. However, the degree of solubility enhancement was often limited by the formation of only a 1:1 complex and a low complexation [...] Read more.
Hydroxypropyl-β-cyclodextrin (HP-β-CD) is commonly used as a complexation reagent to solubilize compounds with poor aqueous solubility to improve in vivo dosing. However, the degree of solubility enhancement was often limited by the formation of only a 1:1 complex and a low complexation constant (K). Such a limitation can be significantly improved by the formation of 1:2 complexes in some cases. Despite the understanding of the solubility advantage of the formation of the 1:2 complexes, there is no systematic understanding that could drive for the formation of 1:2 complexes. Thus, in most cases, the formation of 1:2 complexes was limited by observation bases. In this study, we pioneer the usages of molecular dynamics (MD) simulation to understand the phenomena of a model drug of celecoxib (CCB) and HP-β-CD. It has been reported that celecoxib (CCB) forms 1:1 complexes with cyclodextrin in solution; however, some data suggest the existence of a 1:2 complex. The simulation results suggest that a transition state of CCB and HP-β-CD may exit at a higher temperature of CCB and HP-β-CD; a model drug, such as celecoxib (CCB), that is known to form 1:1 complexes can achieve a higher degree of complexation (1:2) and obtain much improved solubility when the same amount of cyclodextrin was used and demonstrated in vitro. The simulation results of CCB and HP-β-CD could be a model system that may provide important insights into the inclusion mechanism. Full article
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Open AccessArticle The Influence of Pressure on the Intrinsic Dissolution Rate of Amorphous Indomethacin
Pharmaceutics 2014, 6(3), 481-493; doi:10.3390/pharmaceutics6030481
Received: 7 July 2014 / Revised: 5 August 2014 / Accepted: 7 August 2014 / Published: 20 August 2014
Cited by 3 | PDF Full-text (1167 KB) | HTML Full-text | XML Full-text
Abstract
New drug candidates increasingly tend to be poorly water soluble. One approach to increase their solubility is to convert the crystalline form of a drug into the amorphous form. Intrinsic dissolution testing is an efficient standard method to determine the intrinsic dissolution [...] Read more.
New drug candidates increasingly tend to be poorly water soluble. One approach to increase their solubility is to convert the crystalline form of a drug into the amorphous form. Intrinsic dissolution testing is an efficient standard method to determine the intrinsic dissolution rate (IDR) of a drug and to test the potential dissolution advantage of the amorphous form. However, neither the United States Pharmacopeia (USP) nor the European Pharmacopeia (Ph.Eur) state specific limitations for the compression pressure in order to obtain compacts for the IDR determination. In this study, the influence of different compression pressures on the IDR was determined from powder compacts of amorphous (ball-milling) indomethacin (IND), a glass solution of IND and poly(vinylpyrrolidone) (PVP) and crystalline IND. Solid state properties were analyzed with X-ray powder diffraction (XRPD) and the final compacts were visually observed to study the effects of compaction pressure on their surface properties. It was found that there is no significant correlation between IDR and compression pressure for crystalline IND and IND–PVP. This was in line with the observation of similar surface properties of the compacts. However, compression pressure had an impact on the IDR of pure amorphous IND compacts. Above a critical compression pressure, amorphous particles sintered to form a single compact with dissolution properties similar to quench-cooled disc and crystalline IND compacts. In such a case, the apparent dissolution advantage of the amorphous form might be underestimated. It is thus suggested that for a reasonable interpretation of the IDR, surface properties of the different analyzed samples should be investigated and for amorphous samples the IDR should be measured also as a function of the compression pressure used to prepare the solid sample for IDR testing. Full article
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Open AccessArticle Bioadhesive Mini-Tablets for Vaginal Drug Delivery
Pharmaceutics 2014, 6(3), 494-511; doi:10.3390/pharmaceutics6030494
Received: 4 July 2014 / Revised: 13 August 2014 / Accepted: 15 August 2014 / Published: 27 August 2014
Cited by 5 | PDF Full-text (863 KB) | HTML Full-text | XML Full-text
Abstract
Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model [...] Read more.
Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug. Full article
(This article belongs to the Special Issue Dosage Forms and Delivery Systems for Vaginal Therapy)
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Open AccessArticle Firmness Perception Influences Women’s Preferences for Vaginal Suppositories
Pharmaceutics 2014, 6(3), 512-529; doi:10.3390/pharmaceutics6030512
Received: 23 June 2014 / Revised: 23 August 2014 / Accepted: 26 August 2014 / Published: 10 September 2014
Cited by 2 | PDF Full-text (905 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Microbicides are being actively researched and developed as woman-initiated means to prevent HIV transmission during unprotected coitus. Along with safety and efficacy, assessing and improving compliance is a major area of research in microbicide development. We have developed carrageenan-based semisoft vaginal suppositories [...] Read more.
Microbicides are being actively researched and developed as woman-initiated means to prevent HIV transmission during unprotected coitus. Along with safety and efficacy, assessing and improving compliance is a major area of research in microbicide development. We have developed carrageenan-based semisoft vaginal suppositories and have previously evaluated how physical properties such as firmness, size and shape influence women’s willingness to try them. Firmness has previously been quantified in terms of small-strain storage modulus, G’, however large-strain properties of the gels may also play a role in the firmness perception. In the current study we prepared two sets of suppositories with the same G’ but different elongation properties at four different G’ values (250, 2500, 12,500, 25,000 Pa): For convenience we refer to these as “brittle” and “elastic”, although these terms were never provided to study participants. In the first of two tests conducted to assess preference, women compared pairs of brittle and elastic suppositories and indicated their preference. We observed an interaction, as women preferred brittle suppositories at lower G’ (250, 2500 Pa) and elastic ones at a higher G’ (25,000 Pa). In the second test, women evaluated samples across different G’, rated the ease-of-insertion and willingness-to-try and ranked the samples in order of preference. Brittle suppositories at G’ of 12,500 Pa were most preferred. In vitro studies were also conducted to measure the softening of the suppositories in contact with vaginal simulant fluid (VSF). Release of antiretroviral drug tenofovir in VSF was quantified for the brittle and elastic suppositories at G’ of 12,500 Pa to determine the effect of suppository type on release. The initial rate of release was 20% slower with elastic suppositories as compared to brittle suppositories. Understanding how different physical properties simultaneously affect women’s preferences and pharmacological efficacy in terms of drug release is required for the optimization of highly acceptable and efficacious microbicides. Full article
(This article belongs to the Special Issue Dosage Forms and Delivery Systems for Vaginal Therapy)
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Open AccessArticle Characterization of Commercially Available Vaginal Lubricants: A Safety Perspective
Pharmaceutics 2014, 6(3), 530-542; doi:10.3390/pharmaceutics6030530
Received: 21 July 2014 / Revised: 5 September 2014 / Accepted: 9 September 2014 / Published: 22 September 2014
Cited by 7 | PDF Full-text (1126 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Vaginal lubricants are widely used by women to help solve intercourse difficulties or as enhancers, but recent reports raise questions about their safety. Twelve commercially available gel products were tested for pH value, pH buffering capacity, osmolality and cytotoxicity relevant to vaginal [...] Read more.
Vaginal lubricants are widely used by women to help solve intercourse difficulties or as enhancers, but recent reports raise questions about their safety. Twelve commercially available gel products were tested for pH value, pH buffering capacity, osmolality and cytotoxicity relevant to vaginal delivery. Obtained data were analyzed in light of the recent Advisory Note by the World Health Organization (WHO) for personal lubricants to be concomitantly used with condoms. Results showed that most products do not comply with pH and osmolality recommended standards, thus posing a potential hazard. Four products presented values of osmolality around three-times higher than the maximum acceptable limit of 1200 mOsm/kg. In vitro cell testing further identified substantial cytotoxicity even at 1:100 dilutions for three products, contrasting with no significant effect of up to at least a 1:5 dilution of a Universal Placebo gel. However, no direct correlation between these last results and pH or osmolality was found, thus suggesting that the individual toxicity of specific formulation components plays an important role in the outcome of a particular product. Although further assessment is required, these results highlight potential safety issues related to the formulation of commercially available vaginal lubricants. Full article
(This article belongs to the Special Issue Dosage Forms and Delivery Systems for Vaginal Therapy)
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Review

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Open AccessReview Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives
Pharmaceutics 2014, 6(3), 378-415; doi:10.3390/pharmaceutics6030378
Received: 18 February 2014 / Revised: 20 June 2014 / Accepted: 24 June 2014 / Published: 10 July 2014
Cited by 3 | PDF Full-text (1638 KB) | HTML Full-text | XML Full-text
Abstract
Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated [...] Read more.
Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. Full article
(This article belongs to the Special Issue Respiratory and Nasal Drug Delivery)
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Open AccessReview Encapsulated Cells Expressing a Chemotherapeutic Activating Enzyme Allow the Targeting of Subtoxic Chemotherapy and Are Safe and Efficacious: Data from Two Clinical Trials in Pancreatic Cancer
Pharmaceutics 2014, 6(3), 447-466; doi:10.3390/pharmaceutics6030447
Received: 24 March 2014 / Revised: 2 July 2014 / Accepted: 30 July 2014 / Published: 11 August 2014
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Abstract
Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome [...] Read more.
Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more. Full article
(This article belongs to the Special Issue Microencapsulation Technology Applied to Pharmaceutics 2014)
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