Administration Route Dependent Bioavailability of Interferon-α and Effect of Bile Salts on the Nasal Absorption

Abstract

Administration route dependent bioavailability of recombinant human interferon alpha (IFN-α) and effect of seven bile salts and polyoxyethylene-9-lauryl ether (BL-9) on nasal absorption of IFN-a were studied in rats. IFN-a (1.5 × 10 ⁷ IU/kg) was administered through iv, pv, po and ip routes and AUC of the routes were compared. As a result, it was found that IFN-α is extracted almost completely during its passage through the GI lumen, and is not absorbed from the GI lumen. Moreover, IFN-α sparingly transported through the GI lumen suffers additional extraction by the GI mucosa (57%) and the liver (8%) consecutively and only about 40% of it can reach the systemic circulation. Therefore, a high bioavailability of IFN-a cannot be expected through the oral route even with the aid of absorption enhancers. On the other hand, significant absorption of IFN-α could be attained through the nasal route with some absorption enhancers (1% w/v). Among the enhancers examined, sodium cholate (CH), sodium glycocholate (GC), sodium taurocholate (TC), sodium glycodeoxycholate (GDC), sodium taurodeoxycholate (TDC) and BL-9 increased the nasal bioavailability of IFN-a. However, sodium dehydrocholate (DHC) and sodium deoxycholate (DOC) did not show such effect. Nasal bioavailability of IFN-a was increased up to 32.3 (± 15.5)% by 1% TC. The enhancing effect of TC was significantly (p<0.05) greater than those of CH, DOC, DHC and BL-9. TC and GC seemed to be potential candidates for the nasal absorption enhancers of IFN-α, considering that they are reportedly less toxic than GDC and TDC.     

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl β cyclodextrin inclusion complex (AM-HPβCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29–34?°c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120?min (99.1?±?0.44%w/v). Dissolution in simulated nasal fluid was 92.33?±?0.15%w/v at the end of 120?min. Locomotor activity was improved with nasal gel containing AM-HPβCD as compared to AM and AM-HPβCD oral solution in rats. C_max for nasal gel was found to be more (9?ng/ml) as compared to AM-HPβCD (5.5?ng/mL) and oral standard solution (2?ng/ml). T_max was found to be 1.5?h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.     

COMPARISON OF NASAL INSULIN POWDERS PREPARED BY SUPERCRITICAL FLUID AND FREEZE-DRYING TECHNIQUES

ABSTRACT

In this study, the effect of drug loading on the nasal absorption of insulin was determined. Human insulin was loaded into different drug carriers by two methods: supercritical fluid processing and freeze-drying. The powder formulations were characterized and then evaluated after nasal administration to alloxan induced diabetic rabbits at a dose of 5U/kg and 7.5U/kg. The blood glucose levels and serum insulin levels were monitored for five hours after administration of insulin formulations. The drug carriers evaluated were: ammonium glycyrrhizinate (AG), polyacrylic acid (PAA), cross-linked polyacrylic acid (CPAA), polyethylene oxide (PEO) and chitosan (CHTN).

Nasal administration of AG infused with insulin by carbon dioxide resulted in absolute bioavailability of 9.81% as compared to 2.86% observed with same powder loaded with insulin by freeze-drying. 8.05% bioavailability was obtained with PAA powder loaded with insulin by carbon dioxide as compared to much lower absorption seen with freeze-dried formulation. Similarly a two fold increase in absolute bioavailability was observed when carbon dioxide infused CPAA powder formulation was compared to the lyophilized powder. Nasal administration of PEO and CHTN loaded with insulin by carbon dioxide resulted in bioavailabilities of 1.55% and 1. 18% respectively.

The drug-loading process seems to have a significant effect on nasal absorption of insulin. The powders loaded with insulin by carbon dioxide infusion resulted in significantly higher absorption. The exact mechanism is still not known and a possible explanation for increased absorption may be due to improved stability of insulin in carbon dioxide infused formulations. Among the powders evaluated, polyacrylic acid and ammonium glycyrrhizinate prepared by carbon dioxide infusion as drug-loading method seem to offer good potential for development of nasal powder dosage forms for insulin.     

COMPARISON OF NASAL INSULIN POWDERS PREPARED BY SUPERCRITICAL FLUID AND FREEZE-DRYING TECHNIQUES

In this study, the effect of drug loading on the nasal absorption of insulin was determined. Human insulin was loaded into different drug carriers by two methods: supercritical fluid processing and freeze-drying. The powder formulations were characterized and then evaluated after nasal administration to alloxan induced diabetic rabbits at a dose of 5U/kg and 7.5U/kg. The blood glucose levels and serum insulin levels were monitored for five hours after administration of insulin formulations. The drug carriers evaluated were: ammonium glycyrrhizinate (AG), polyacrylic acid (PAA), cross-linked polyacrylic acid (CPAA), polyethylene oxide (PEO) and chitosan (CHTN).

Nasal administration of AG infused with insulin by carbon dioxide resulted in absolute bioavailability of 9.81% as compared to 2.86% observed with same powder loaded with insulin by freeze-drying. 8.05% bioavailability was obtained with PAA powder loaded with insulin by carbon dioxide as compared to much lower absorption seen with freeze-dried formulation. Similarly a two fold increase in absolute bioavailability was observed when carbon dioxide infused CPAA powder formulation was compared to the lyophilized powder. Nasal administration of PEO and CHTN loaded with insulin by carbon dioxide resulted in bioavailabilities of 1.55% and 1. 18% respectively.

The drug-loading process seems to have a significant effect on nasal absorption of insulin. The powders loaded with insulin by carbon dioxide infusion resulted in significantly higher absorption. The exact mechanism is still not known and a possible explanation for increased absorption may be due to improved stability of insulin in carbon dioxide infused formulations. Among the powders evaluated, polyacrylic acid and ammonium glycyrrhizinate prepared by carbon dioxide infusion as drug-loading method seem to offer good potential for development of nasal powder dosage forms for insulin.     

Influence of Bile Salts on the Permeability Through the Nasal Mucosa of Rabbits of Insulin in Comparison with Dextran Derivatives

Abstract

The nasal drug absorption and the effect of absorption promoters have been studied in rabbits. Nasal mucosa excised from rabbits was mounted as a flat sheet in an in vitro chamber. The result indicates that the change in the porosity of the membrane by pretreatment with bile salts increased the permeability coefficient of sodium chloride in the nasal membrane. The permeabilities of dextran derivatives were enhanced by pretreatment with sodium glycocholate (GC). The permeability coefficient (P) of fluorescein isothiocyanate diethylaminoethyl dextran     

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Abstract

Context: Brain disorders remain the world's leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood–brain barrier (BBB), thus impeding treatment of these conditions.

Objective: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain.

Methods: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown.

Result and conclusion: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.     

Influence of Bile Salts on the Permeability Through the Nasal Mucosa of Rabbits of Insulin in Comparison with Dextran Derivatives

The nasal drug absorption and the effect of absorption promoters have been studied in rabbits. Nasal mucosa excised from rabbits was mounted as a flat sheet in an in vitro chamber. The result indicates that the change in the porosity of the membrane by pretreatment with bile salts increased the permeability coefficient of sodium chloride in the nasal membrane. The permeabilities of dextran derivatives were enhanced by pretreatment with sodium glycocholate (GC). The permeability coefficient (P) of fluorescein isothiocyanate diethylaminoethyl dextran     

Microscopic Cascading Devices for Boosting Mucus Penetration in Oral Drug Delivery—Micromotors Nesting Inside Microcontainers

In the case of macromolecules and poorly permeable drugs, oral drug delivery features low bioavailability and low absorption across the intestinal wall. Intestinal absorption can be improved if the drug formulation could be transported close to the epithelium. To achieve this, a cascade delivery device comprising Magnesium-based Janus micromotors (MMs) nesting inside a microscale containers (MCs) has been conceptualized. The device aims at facilitating targeted drug delivery mediated by MMs that can lodge inside the intestinal mucosa. Loading MMs into MCs can potentially enhance drug absorption through increased proximity and unidirectional release. The MMs will be provided with optimal conditions for ejection into any residual mucus layer that the MCs have not penetrated. MMS confined inside MCs propel faster in the mucus environment as compared to non-confined MMs. Upon contact with a suitable fuel, the MM-loaded MC itself can also move. An in vitro study shows fast release profiles and linear motion properties in porcine intestinal mucus compared to more complex motion in aqueous media. The concept of dual-acting cascade devices holds great potential in applications where proximity to epithelium and deep mucus penetration are needed.     

Pharmacodynamic Comparison of a Nasal Formulation of Verapamil and Intravenous and Oral Dosage Forms

The nasal route has been shown to be effective for the administration of numerous drugs in order to improve drug bioavailability. A nasal gel of verapamil hydrochloride was formulated and evaluated pharmacodynamically in humans, using electrocardiographic results, with comparison to oral and IV routes. Seven volunteers were involved in the study and the pharmacodynamic parameters were evaluated statistically. Experimental nasal gel showed similar pharmacodynamic results with the intravenous route, which is a hint to the reduction in verapamilinduced first-pass metabolism. However, oral route of administration showed a tendency of less efficacy. No reasonable effect of verapamil could be obtained with the placebo group.     

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 2³ full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1?h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.     

Calculation procedures and HPLC method for analysis of the lipophilicity of acyclovir esters

Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Selected ACV esters including acetyl (Ac-), isobutyryl (iBut-), pivaloyl (Piv-), ethoxycarbonyl (Etc-) and nicotinoyl (Nic-) were synthesized, and their lipophilicity was determined by the high-performance liquid chromatography (HPLC) RP method. Statistical analyses of the comparative values of log?P and clog?P were carried out using computational methods. It was proved that the AC log?P algorithm can be useful for the analysis of these compounds and has a statistically justified application in the assessment of the quantitative structure–activity relationship. Moreover, the lipophilicity determined by the HPLC method appears as follows: ACV?相似文献   

Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease

Abstract

Parkinson’s disease is a degenerative disorder of the central nervous system (CNS). The most obvious symptoms are movement-related such as shaking, rigidity, slowness of movement and difficulty with walking, rigid muscular movements and difficulty in chewing and swallowing especially solid dosage forms. Ropinirole is an anti-Parkinson drug that has low oral bioavailability which is primarily due to first-pass metabolism. The objective of proposed work was to increase bioavailability of ropinirole and avoid patient discomfort by formulating thermoreversible in situ nasal gel. Thermoreversible nasal gels were prepared by cold method using Pluronic F-127 and hydroxy methyl propyl cellulose (HPMC K4M) as gelling agents. Formulations were evaluated for various parameters such as drug content, pH, gelling time, gelling temperature, gel strength, mucoadhesive force, ex vivo diffusion, histological studies and in vivo bioavailability. Formulations displayed gelation at nasal temperature and the gelation time was found to be less than mucociliary clearance time. The nasal residence time was seen to be increased due to mucoadhesion and increased gel strength. The nasal gel formulations showed ex vivo drug release between 56–100% in 5?h. Histological study of sheep nasal mucosa revealed that the gel had a protective effect on the mucosa unlike plain ropinirole which showed evidence of moderate cellular damage. A fivefold increase in bioavailability in brain was observed on nasal administration as compared to IV route. Thermoreversible in situ nasal gel was found to a promising drug delivery for Parkinsonian patients.     

A Simplified Rat Model for Studying Nasal Drug Absorption

Abstract

A simple and rapid rat model for studying nasal drug absorption was developed. In this model, a solution of the test drug, propranolol hydrochloride, was gradually deposited into the nasal cavity of an anesthetized rat through a PE-20 polyethylene catheter connected to a tuberculin syringe via a 30 gauge needle. The extent of drug bioavailability was assessed by measuring propranolol blood levels and the changes in heart rate. For comparative purposes, identical experiments were repeated using the intravenous route of administration, an established rat model requiring surgery, and the proposed model after tracheal cannulation and esophageal li-gation. Although the pharmacokinetic parameters for the various models tested indicated bioavailabilities that were quite similar to that obtained by the intravenous route of administration, the drop in heart rates appeared to be more pronounced with the proposed model than with any of the other two models. In addition to its simplicity, the proposed rat model represents a less stressful and more physiological means of delivering a drug by the nasal route.     

The Intranasal Absorption of the Quaternary Ammonium Compounds Neostigmine Bromide and Tubocurarine Chloride in the Rat

The systemic absorptions of the quaternary ammonium compounds, neostigmine bromide and (+)-tubocurarine chloride, from the nasal cavity were compared in the adult male rat with those obtained by the oral and intravenous routes. By the oral route, neostigmine bromide was absorbed to a limited extent and tubocurarine chloride demonstrated undetectable plasma levels. In contrast, use of the intranasal route resulted in plasma drug levels that were either significantly higher or readily detectable. Greater systemic absorptions and, thereby, improved bioavailabilities were achieved by coadministering the title drugs with sodium glycocholate, a surfactant, or with amastatin, an aminopeptidase inhibitor. For both drugs, bioavailabilities in the presence of amastatin were greater than in the presence of sodium glycocholate (≥90% vs. ≥70%). Differences in the rate and extent of absorption of the quaternary ammonium compounds across the nasal mucosa appeared to reflect differences in molecular weight.     

Microneedles for transdermal drug delivery: a systematic review

Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500?Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.     

The Use of Lipid-Based Formulations to Increase the Oral Bioavailability of Panax Notoginseng Saponins Following a Single Oral Gavage to Rats

Purpose: This article was intended to improve the absorption of ginsenoside Rg1 and Rb1 of Panax notoginseng saponins (PNS). Methods: PNS-Phospholipid complex and a lipid-based formulation by dissolving the complex in the medium chain fattyglycerides were prepared, and their oral relative bioavailability was determined in rats and compared with an aqueous solution of PNS for each component. Results: The study gave evidence that the phospholipids could combine with the two active constitutes of PNS and form a PNS-phospholipid complex. The complex efficiently increased the solubility of hydrophilic ginsenoside Rg1 and Rb1 in some selected hydrophobic esters, such as fatty glycerides, and constructed the lipid-based formulations of PNS. The experimental result in rats in vivo showed that the oral relative bioavailability was enhanced remarkably by these lipid-based formulations composed of the PNS-Phospholipid complex and various esters. The absorption enhancement of the medium-chain glyceride (Labrafac cc and Capmul MCM (3:1)) was somewhat greater than that of other fatty glyceride. The area under the plasma concentration-time curve (AUC) of ginsenoside Rg1 and Rb1 of the PNS-complex in the medium-chain glyceride were 27.38 μg.mL-1.h and 600.08 μg.mL-1.h, compared with 2.52 μg.mL-1.h and 92.29 μg.mL-1.h of the PNS aqueous solution, respectively. Conclusions: The oral relative bioavailability of ginsenoside Rg1 and Rb1 of PNS was enhanced remarkably by the lipid-based formulations. These findings reveal a new strategy to increase oral bioavailability by lipophilicity enhancement for some highly water-soluble but poorly absorbed drugs.     

A Simplified Rat Model for Studying Nasal Drug Absorption

A simple and rapid rat model for studying nasal drug absorption was developed. In this model, a solution of the test drug, propranolol hydrochloride, was gradually deposited into the nasal cavity of an anesthetized rat through a PE-20 polyethylene catheter connected to a tuberculin syringe via a 30 gauge needle. The extent of drug bioavailability was assessed by measuring propranolol blood levels and the changes in heart rate. For comparative purposes, identical experiments were repeated using the intravenous route of administration, an established rat model requiring surgery, and the proposed model after tracheal cannulation and esophageal li-gation. Although the pharmacokinetic parameters for the various models tested indicated bioavailabilities that were quite similar to that obtained by the intravenous route of administration, the drop in heart rates appeared to be more pronounced with the proposed model than with any of the other two models. In addition to its simplicity, the proposed rat model represents a less stressful and more physiological means of delivering a drug by the nasal route.     

The use of lipid-based formulations to increase the oral bioavailability of Panax notoginseng saponins following a single oral gavage to rats

Purpose: This article was intended to improve the absorption of ginsenoside Rg1 and Rb1 of Panax notoginseng saponins (PNS). Methods: PNS-Phospholipid complex and a lipid-based formulation by dissolving the complex in the medium chain fattyglycerides were prepared, and their oral relative bioavailability was determined in rats and compared with an aqueous solution of PNS for each component. Results: The study gave evidence that the phospholipids could combine with the two active constitutes of PNS and form a PNS-phospholipid complex. The complex efficiently increased the solubility of hydrophilic ginsenoside Rg1 and Rb1 in some selected hydrophobic esters, such as fatty glycerides, and constructed the lipid-based formulations of PNS. The experimental result in rats in vivo showed that the oral relative bioavailability was enhanced remarkably by these lipid-based formulations composed of the PNS-Phospholipid complex and various esters. The absorption enhancement of the medium-chain glyceride (Labrafac cc and Capmul MCM (3:1)) was somewhat greater than that of other fatty glyceride. The area under the plasma concentration-time curve (AUC) of ginsenoside Rg1 and Rb1 of the PNS-complex in the medium-chain glyceride were 27.38 μg.mL-1.h and 600.08 μg.mL-1.h, compared with 2.52 μg.mL-1.h and 92.29 μg.mL-1.h of the PNS aqueous solution, respectively. Conclusions: The oral relative bioavailability of ginsenoside Rg1 and Rb1 of PNS was enhanced remarkably by the lipid-based formulations. These findings reveal a new strategy to increase oral bioavailability by lipophilicity enhancement for some highly water-soluble but poorly absorbed drugs.     

Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology

Carfentanil (CFTN), a derivative of fentanyl, is highly effective as an analgesic, but its relatively poor solubility in water has limited its nasal application. The objective of this study was to develop the new CFTN-CD inclusion technology to increase the solubility of CFTN. The inclusion compound CFTN–DM-β-CD was prepared by the ultrasonic method and characterized using X-ray powder diffraction and morphological shapes analysis (the scanning electron microscopy). The in vitro dissolution profiles of CFTN–DM-β-CD were assessed in hydrochloric acid and phosphate buffer. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with CFTN–DM-β-CD (250?µg/kg) by intravenous, intramuscular injection, oral, or nasal drops. The results showed that CFTN was successfully enveloped by DM-β-CD. The in vitro cumulative dissolution of CFTN–DM-β-CD was obviously enhanced compared to free CFTN in two buffers. Nasal ciliotoxicity studies have shown that the CFTN–DM-β-CD does not exhibit higher nasal ciliotoxicity than that of free CFTN. Pharmacokinetic studies demonstrated that CFTN–DM-β-CD by nasal administration was absorbed more rapidly and has higher C_max and bioavailability than that of either intramuscular injection or oral administration. In conclusion, the CFTN–DM-β-CD nasal spray was shown to be a relatively safe dosage form for the rapid and effective intranasal delivery of CFTN.     

Evaluation of salmon calcitonin (sCT) enteric-coated capsule for enhanced absorption and GI tolerability in rats

Background: Considering the chronic and repeated nature of salmon calcitonin (sCT) therapy, the oral route is a preferred route of administration. But, the oral bioavailability of sCT is very low due to enzymatic degradation and poor permeation across intestinal epithelial cells. It was the aim of this study to investigate the pharmacodynamic (PD), pharmacokinetic (PK), and mucosal injury characteristic of sCT oral delivery system. Method: In this study, PD experiments were performed to find a suitable releasing region of sCT, an effect absorption enhancer, and an optimal mass ratio of sCT/enhancer. In addition, the PK experiments were designed to validate the absorption enhancement of this oral delivery system. Histopathological evaluations on the intestinal mucosa were carried out to assess any potential toxicity of the absorption enhancer. Results: Through the PD research, we determined that oral sCT enteric-coated capsules containing sCT and citric acid (CA) with a ratio of 1:20 may be an adaptable delivery. PK study further proved that the oral absorption of sCT was enhanced from this delivery system. Finally, no damage on intestinal mucosa was observed when rats received the delivery system containing CA for up to 7 days. Conclusion: These results suggested that enteric-coated capsules with a certain amount of CA might give enhanced oral delivery of peptide drugs like sCT.