Dissolution Chamber for Small Drug Delivery System in the Periodontal Pocket.

Existing dissolution chambers have relatively large volume compared to the size of the periodontal pocket. A small volume dissolution method that simulates the physiological release environment for periodontal drug delivery is needed. The objectives were to construct a small, more physiologically relevant, dissolution chamber and investigate the properties of the new dissolution chamber for the assessment of sustained drug release systems in periodontal delivery. Flow-through dissolution chambers were constructed using three-dimensional (3D) printing. Drug release experiments were performed using the dissolution chamber and a commercially available long-acting periodontal insert product, PerioChip®. Similar experiments were performed under more traditional larger volume bulk solution conditions for comparison. Computer simulations and experimental results showed that drug clearance from the dissolution chamber was fast compared to drug release from the periodontal product. Drug clearance from the flow-through dissolution chamber and drug release from the sustained release product in the chamber were related to the dissolution medium flow rate and chamber volume. Drug release in the flow-through chamber was slower than that observed in bulk solution, but approached it when the medium flow rate increased. The presence of trypsin in the dissolution medium enhanced drug release from the product. A flow-through dissolution system was constructed that could evaluate drug release from a sustained release product in a small dimension environment by modifying the flow rate and composition of the dissolution medium.

Influencing factors on gelatin matrix for chlorhexidine delivery.

OBJECTIVE: The objective was to evaluate the influencing factors in the fabrication of gelatin matrix (gelatin chips) for drug delivery. The attributes affecting drug release characteristics of the gelatin products were examined. SIGNIFICANCE: Understanding the attributes that affect drug release from gelatin matrix could provide the knowledge base for the development, manufacturing, and performance evaluation of gelatin-based drug products for sustained drug delivery. METHODS: Chlorhexidine (CHX) was the model drug in the gelatin-product testing. The gelatin products were fabricated by two methods: a single-pot mixing of all the components and a two-step gelatin crosslinking followed by drug loading. Different gelatin types (Type A porcine and Type B bovine), glutaraldehyde (GTA) crosslinking conditions, glycerin concentration, and CHX concentration in drug loading and loading time were used to fabricate the products. The cumulative amounts of CHX release from the gelatin products were determined using in vitro release testing (IVRT). RESULTS: The attributes affecting CHX release from the gelatin products were gelatin type, GTA crosslinking, and CHX loading concentration. The fabrication methods (two-step method of gelatin crosslinking and drug loading by equilibration vs. direct mixing of the components) also affected CHX release. Other attributes such as glycerin and CHX loading time did not show significant effects on drug release under the conditions studied. In addition, the results in the two IVRT methods employed in this study were comparable. CONCLUSION: Gelatin products of qualitative (Q1) and quantitative (Q2) differences could lead to different drug release behaviors. Drug release was also affected by the ingredient mixing steps during gelatin chip fabrication.

Reduction in the appearance of facial hyperpigmentation by topical N-undecyl-10-enoyl-L-phenylalanine and its combination with niacinamide.

OBJECTIVES: N-undecyl-10-enoyl-L-phenylalanine (Sepiwhite), N-undecylenoyl phenylalanine), a reported alpha-melanocyte-stimulating hormone (MSH) receptor antagonist, has been observed to reduce melanin production in cultured melanocytes. In other testing, niacinamide has been found to inhibit melanosome transfer in cultured cells and to reduce the appearance of hyperpigmented spots in clinical studies. Since these two agents function by different mechanisms, we conducted two studies to determine if their combination is more effective than niacinamide alone in reducing facial hyperpigmentation. METHODS: Two double-blind, 10-week (2-week washout + 8-week treatment), left-right randomized, split-face clinical studies were conducted. In one, two groups of Japanese women applied one of two pairs of test emulsion formulations: a vehicle control and a 5% niacinamide formulation (n= 40), or a 5% niacinamide and a 5% niacinamide plus 1%N-undecylenoyl phenylalanine formulation (n = 40). Each formulation was applied to the randomly assigned side of the face. In the second study, Caucasian women applied one of three emulsions: vehicle control, 5% niacinamide formulation, or combination 5% niacinamide plus 1%N-undecylenoyl-phenylalanine formulation to the randomly assigned side of the face (n = approximately 60 treatment sites per formulation). In both studies, hyperpigmented spots were evaluated at weeks 4 and 8 by quantitative image analysis. RESULTS: In both studies, the combination formulation was significantly more effective than the vehicle and the 5% niacinamide formulation in reducing the appearance of hyperpigmentation after 8 weeks. CONCLUSIONS: The combination of 5% niacinamide and 1%N-undecylenoyl phenylalanine is an effective anti-aging technology for use on facial skin.

Voluntary consumption of ethyl oleate reduces food intake and body weight in rats.

Previous studies have shown that administration of the fatty acids, linoleic and oleic acid, either by intragastric or intraintestinal infusion, suppresses food intake and body weight in rats. While still not fully understood, gut-mediated satiety mechanisms likely are potential effectors of this robust response to gastrointestinal fatty acid infusions. The objective of this study was to assess the effects of voluntary access to an oleic acid derivative, ethyl oleate (EO), on subsequent food intake and body weight in rats. Animals were randomized either to a 12.5% EO diet or a soybean oil diet as a "breakfast," followed either by two one-hour or one five-hour access periods to standard rodent diet, and food intake and body weights were collected. Across 14 days access, rats consuming EO on both feeding schedules gained less weight and consumed less total kilocalories than rats consuming the SO diet. Further, plasma levels of glucose and insulin were comparable in both EO and SO diet groups. In summary, EO was found to increase weight loss in rats maintained on a 75% food-restriction regimen, and attenuate weight-gain upon resumption of an ad-libitum feeding regimen. These data indicate that voluntary access to EO promoted short-term satiety, compared to SO diet, and that these effects contributed to an important and novel attenuated weight gain in EO-fed animals.

Reduction in the appearance of facial hyperpigmentation by topical N-acetyl glucosamine.

Glucosamine has been reported to inhibit melanin production in melanocyte culture. It thus has a potential to reduce hyperpigmentation via topical use. Due to stability limitations of glucosamine, we chose to clinically evaluate the stable derivative N-acetyl glucosamine (NAG). Based on in vitro Franz cell testing, NAG is a good skin penetrant. In an 8-week, double-blind, placebo-controlled, left-right randomized, split-face clinical test, topical 2% NAG reduced the appearance of facial hyperpigmentation. In a second clinical study involving the topical combination of 2% NAG with 4% niacinamide, an agent previously shown to be clinically active, the effect on hyperpigmentation was greater. Both of these agents are well tolerated by the skin. This high tolerance coupled with relative ease of formulation and stability in solution make NAG, especially in combination with niacinamide, a suitable cosmetic ingredient for use in skin care products dealing with issues of skin hyperpigmentation.

Suppression of food intake by GI fatty acid infusions: roles of celiac vagal afferents and cholecystokinin.

We have found that jejunal infusions of long-chain fatty acids, linoleic acid (LA) and oleic acid (OA), and gastric infusions of a fatty acid ethyl ester, ethyl oleate (EO), produce long-lasting suppression of total caloric intake. This effect is not seen in response to jejunal infusions of medium-chain fatty acids or medium- or long-chain triglycerides. Multiunit recordings have shown that intestinal infusions of LA or OA strongly activate celiac vagal afferents. Truncal vagotomy (TVX) and selective celiac-branch vagotomy (CVX) are equally effective in attenuating, but not eliminating, suppression of food intake by LA and EO. These outcomes suggest that intraintestinal fatty acids reduce intake by activation of vagal mechanisms, critically involving afferent fibers within the celiac branches, as well as unidentified nonvagal mechanisms. The role of cholecystokinin (CCK) in mediating the activation of celiac vagal afferents is suggested by studies showing that (1) inhibition of food intake by CCK-8 administration is attenuated after CVX but robust after celiac-spared vagotomy (CSV), (2) multiunit activity of celiac vagal afferents is increased by CCK-8 administration, and (3) activation of celiac fibers by intestinal LA infusion is severely attenuated by the CCK(A) antagonist lorglumide.

Truncal and hepatic vagotomy reduce suppression of feeding by jejunal lipid infusions.

Two experiments investigated mechanisms underlying the decrease in food intake produced by lipid infusions into the jejunum. In Experiment 1, male Sprague-Dawley rats with truncal abdominal vagotomy (TVx), selective hepatic-branch vagotomy (HVx), or sham vagotomy received repeated 7 h infusions of linoleic acid (LA), corn oil (CO), or saline through indwelling jejunal catheters. Cumulative food intake was measured at 1, 3, 6, and 23 h. LA and, to a lesser extent, CO suppressed food intake in excess of the caloric value of the load. This effect was eliminated by TVx, which significantly attenuated the suppression of intake produced by both lipids at 3 and 6 h and also at 23 h when LA was infused. HVx attenuated suppression at 23 h on tests with LA and at 3 and 6 h on CO tests. Experiment 2 showed that jejunal infusion of LA had no effect on multi-unit activity of afferent fibers in the left splanchnic nerve in anesthetized rats. Thus, these results provide further evidence that satiating effects of intestinal lipid infusions are mediated by the vagal fibers, some of which lie within the hepatic branch. However, because significant suppression of food intake remained after TVx, and because of the negative results of Experiment 2, these lipid infusions engage as yet unidentified mechanisms independent of the vagus.

Jejunal administration of linoleic acid increases activity of neurons in the paraventricular nucleus of the hypothalamus.

The present experiment examined whether neurons located in the paraventricular nucleus of the hypothalamus (PVN) respond to intestinal infusions of long-chain fatty acids. Single-unit recordings were made of neurons located in and adjacent to the PVN during jejunal administration of linoleic acid. Jejunal administration of linoleic acid increased single-unit activity of neurons located in the PVN but did not affect activity of neurons located in adjacent tissue outside the PVN. The largest increases in neuronal activity were observed in the anterior PVN (0.9-1.3 mm posterior to bregma) compared with the posterior PVN (1.8-2.1 mm posterior to bregma). Jejunal administration of saline failed to affect activity of neurons located either inside or outside the PVN. When the same neurons were subsequently tested for their response to intravenous administration of 2 microg/kg of CCK-8, excitatory responses were more frequently observed than inhibitory responses, but both types of responses were observed regardless of whether neurons were located inside or outside the PVN. In addition, there was no strong correlation between the magnitude of the neuronal response evoked by jejunal administration of linoleic acid compared with intravenous CCK-8. These data suggest that neurons located in the anterior PVN may play a role in the mediation of suppression of food intake produced by intestinal administration of lipids.

The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans.

The absorption, distribution, and excretion of radiolabeled ethyl oleate (EO) was studied in Sprague-Dawley rats after a single, peroral dose of 1.7 or 3.4 g/kg body weight and was compared with a radiolabeled triacylglycerol (TG) containing only oleic acid as the fatty acid (triolein). Both test materials were well absorbed with approximately 70-90% of the EO dose absorbed and approximately 90-100% of the TG dose absorbed. At sacrifice (72 h post-dose), tissue distribution of EO-derived radioactivity and TG-derived radioactivity was similar. The tissue with the highest concentration of radioactivity in both groups was mesenteric fat. The other organs and tissues had very low concentrations of test material-derived radioactivity. Both test materials were rapidly and extensively excreted as CO(2) with no remarkable differences between their excretion profiles. Approximately 40-70% of the administered dose for both groups was excreted as CO(2) within the first 12 h (consistent with beta-oxidation of fatty acids). Fecal elimination of EO appeared to be dose-dependent. At the dose of 1.7 g/kg, 7-8% of the administered dose was eliminated in the feces. At the dose of 3.4 g/kg, approximately 20% of the administered dose was excreted in the feces. Excretion of TG-derived radiolabel in the feces was approximately 2-4% for both doses. Overall, the results demonstrate that the absorption, distribution, and excretion of radiolabeled EO is similar to that of TG providing evidence that the oleic acid moiety of EO is utilized in the body as a normal dietary TG-derived fatty acid. To confirm the expected safety of EO in humans, a total of 235 subjects participated in a 12-week trial where two levels of ethyl oleate in a milk-based beverage were investigated: 8 g/day in a single serving (approximately 0.1 g/kg) and 16 g/day taken in two divided servings (approximately 0.2 g/kg). Adverse events (AEs) were recorded throughout the 12-week trial. In addition, a brief physical exam (including vital signs and body weight), ECGs, fasting serum chemistry profile, serum lipid profile, and urinalysis were performed at baseline and after study completion. Results showed the incidence of reported AEs was similar between the EO groups and the control groups. Analysis of comprehensive laboratory data revealed no EO exposure-related, clinically significant adverse changes in laboratory parameters. These studies demonstrated that EO has a highly favorable safety profile and is well tolerated in the diet.

Responses of hepatic and celiac vagal afferents to intraportal mercaptoacetate in rats fed a high-fat or low-fat diet.

Responses of either hepatic or celiac vagal afferents to intraportal hepatic vein administration of 2-mercaptoacetate (MA) were examined in rats maintained on either a high-fat or low-fat diet. Afferent activity in both hepatic and celiac vagal afferents significantly increased after administration of MA, but the magnitude of these increases did not differ as a function of either diet. Responses of hepatic vagal afferents were highly variable across individual rats, whereas those of celiac vagal afferents were remarkably consistent across individual rats. These data suggest that MA-induced enhanced feeding in rats given a fat-enriched diet does not depend on a stronger hepatic and/or celiac vagal afferent response than that of rats given a low-fat diet.