Nasal administration of low molecular weight heparin

doi:10.1002/jps.10171

Journal of Pharmaceutical Sciences

Volume 91, Issue 7, July 2002, Pages 1707-1714

https://doi.org/10.1002/jps.10171 Get rights and content

Abstract

The main objective of this study was to determine if the systemic absorption of therapeutic amounts of heparin was possible following nasal administration. Sprague‐Dawley rats received nosedrops containing a low molecular weight heparin (LMWH) or unfractionated heparin (UFH) formulated with or without tetradecylmaltoside (TDM). TDM is a nonionic surfactant that has been previously shown to be a potent absorption enhancer in studies with peptide drugs. LMWH/UFH absorption was determined by measuring plasma anti‐Factor Xa activity. The inclusion of 0.25 % TDM in nasal formulations containing LMWH resulted in a significant increase in the C_max and area under the curve (AUC) of anti‐Factor Xa activity when compared to LMWH formulated in saline alone. The addition of TDM to a nasal formulation containing UFH resulted in a much smaller increase in the C_max and the AUC of anti‐Factor Xa activity. The absolute bioavailability of LMWH was increased from 4.0 ± 0.4 % in the absence of TDM to 19 ± 0.3 % in the presence of TDM. The reversibility of the absorption enhancing effect of TDM was studied by applying LMWH nasally 60 or 120 min after the enhancer. The effect of TDM on the nasal epithelia appeared to be rapidly reversible. In conclusion, nasal delivery of LMWH, but not UFH, was successful when an absorption enhancer was included to increase nasal permeability. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1707–1714, 2002

Section snippets

INTRODUCTION

Historically, delivery of large peptides and hydrophilic macromolecules has required parenteral administration. In recent years, the nasal cavity has been widely investigated as a potential site for noninvasive delivery of a large variety of poorly permeable drugs.1., 2., 3., 4. In particular, therapeutic peptide molecules have been extensively studied as potential candidates for nasal drug delivery. Studies have shown size to be an important consideration in nasal drug delivery. Certain

Materials

Enoxaparin (Lovenox) was obtained from Rhone‐Poulenc Rorer (Collegeville, PA) as a sterile solution containing 30 mg enoxaparin sodium (3000 units of anti‐Factor Xa activity) per 0.3 mL. Dalteparin (Fragmin) was purchased from Pharmacia and Upjohn (Kalamazoo, MI) as a sterile solution containing 2500 units of anti‐Factor Xa activity (16 mg dalteparin sodium) per 0.2 mL. Unfractionated heparin was obtained from American Pharmaceutical Partners, Inc. (Los Angeles, CA) as a sterile solution

Nasal Absorption Studies

Nasal formulations containing 100 U of the LMWH, enoxaparin, were initially prepared with and without 0.25 % TDM and applied to anesthetized rats (Figure 2A). It has been previously reported in male Sprague‐Dawley rats that a plasma anti‐Factor Xa level of 0.20 U/mL or higher results in an evident antithrombotic effect.²⁴ Thus, for quantification purposes of the absorption study, plasma anti‐Factor Xa values obtained were categorized as subtherapeutic (< 0.20 U/mL), or therapeutic (> 0.20

CONCLUSIONS

We have demonstrated that therapeutic amounts of the LMWHs, enoxaparin, and dalteparin, can be delivered via the nasal passageway through formulation with the nonionic surfactant, TDM. Further, we have shown that LMWHs formulated with TDM display greater absorption enhancement than UFH formulated with TDM. The PK/PD of enoxaparin following nasal administration differs from that observed following subcutaneous administration. Finally, the enhancing effect of TDM on enoxaparin bioavailability was

Acknowledgements

This work was supported in part by an S.T.T.R Award, ES08933, from the National Institute of Environmental Health Sciences, N.I.H., to CytRx Corporation, Norcross, GA, and the University of Alabama at Birmingham.

REFERENCES (26)

D.‐.Z. Liu et al.
Dodecylphosphocholine‐mediated enhancement of paracellular permeability and cytotoxicity in Caco‐2 cell monolayers
J Pharm Sci
(1999)
R.I. Shulman
Assessment of low‐molecular‐weight heparin trials in cardiology
Pharmacol Ther
(2000)
S. Kaul et al.
Low molecular weight heparin in acute coronary syndrome: Evidence for superior or equivalent efficacy compared with unfractionated heparin?
J Am Coll Cardiol
(2000)
J. Hirsh et al.
Low molecular weight heparin
Blood
(1992)
M.A. Bagger et al.
Nasal bioavailability of peptide T in rabbits: Absorption enhancement by sodium glycocholate and glycofurol
J Pharm Sci
(2001)
Y.W. Chien
Nasal systemic drug delivery
(1989)
L. Illum
Nasal delivery of peptides, factors affecting nasal absorption
A.P. Sayani et al.
Systemic delivery of peptides and proteins across absorptive mucosae
Crit Rev Ther Drug Carrier Sys
(1996)
M.W. Ugwoke et al.
The biopharmaceutical aspects of nasal mucoadhesive drug delivery
J Pharm Pharmacol
(2001)
D.J. Pillion et al.
Insulin delivery in nosedrops: New formulations containing alkylglycosides
Endocrinology
(1994)

D.J. Pillion et al.

Systemic absorption of insulin and glucagon applied to the eyes of rats and diabetic dogs

J Ocul Pharmacol

(1995)

F. Ahsan et al.

Enhanced bioavailibility of calcitonin formulated with alkylglycosides following nasal and ocular administration in rats

Pharm Res

(2001)

M. Maire et al.

Interaction of the membrane proteins and lipids with solubilizing detergents

Biochim Biophys Acta

(2000)

Cited by (62)

Fabrication of the quaternary nanocomplex curcumin-casein-alginate-chitosan as a potential oral delivery system for cancer nutraceutical therapy
2022, Journal of Drug Delivery Science and Technology
Fabricating a nanocargo made from natural constituents for delivering the anticancer drug curcumin orally may offer hope for cancer patients. In this study, protein and polysaccharides were conjugated to form curcumin-loaded casein nanoparticles coated with alginate and chitosan as a double polysaccharide layer “Alg-ch@CurCasNPs”. The developed nanoformulation was characterized in vitro, and its pharmacokinetics and therapeutic efficacy against Ehrlich carcinoma were assessed in vivo. Alg-ch@CurCasNPs exhibited high curcumin encapsulation efficiency (EE = 70%) and controlled release in gastric and intestinal environments. The measured size distribution and zeta potential were 240 ± 20 nm and ±35 mV, respectively. The Alg-ch@CurCasNP morphology showed a monodispersed sphere with a double layer coating. The in vivo pharmacokinetic parameters (C_max, T_max and AUC_0-24) for Alg-ch@CurCasNPs were significantly better than those for free curcumin (Curfree). The in vivo integrated results, including the tumor inhibitory rate (IRT%), genotoxicity and tumor histopathology, collectively demonstrated that repeated oral administration of Alg-ch@CurCasNPs (6 doses/2 weeks-600 mg/kg) in mice showed higher therapeutic efficacy against Ehrlich carcinoma than Curfree treatment. Overall, Alg-ch@CurCasNPs are natural quaternary nanocomplexes that can deliver curcumin orally, enhance its bioavailability and achieve a high therapeutic index in the treatment of cancer.
The Lord of the NanoRings: Cyclodextrins and the battle against SARS-CoV-2
2020, International Journal of Pharmaceutics
A handful of singular structures and laws can be observed in nature. They are not always evident but, once discovered, it seems obvious how to take advantage of them. In chemistry, the discovery of reproducible patterns stimulates the imagination to develop new functional materials and technological or medical applications. Two clear examples are helical structures at different levels in biological polymers as well as ring and spherical structures of different size and composition. Rings are intuitively observed as holes able to thread elongated structures. A large number of real and fictional stories have rings as inanimate protagonists. The design, development or just discovering of a special ring has often been taken as a symbol of power or success. Several examples are the Piscatory Ring wore by the Pope of the Catholic Church, the NBA Championship ring and the One Ring created by the Dark Lord Sauron in the epic story The Lord of the Rings. In this work, we reveal the power of another extremely powerful kind of rings to fight against the pandemic which is currently affecting the whole world. These rings are as small as ~1 nm of diameter and so versatile that they are able to participate in the attack of viruses, and specifically SARS-CoV-2, in a large range of different ways. This includes the encapsulation and transport of specific drugs, as adjuvants to stabilize proteins, vaccines or other molecules involved in the infection, as cholesterol trappers to destabilize the virus envelope, as carriers for RNA therapies, as direct antiviral drugs and even to rescue blood coagulation upon heparin treatment.
“One ring to rule them all. One ring to find them. One ring to bring them all and in the darkness bind them.” J. R. R. Tolkien.
Oral administration of protein nanoparticles: An emerging route to disease treatment
2020, Pharmacological Research
Over the last two decades, developments in nanomedicine have resulted in technical advances with application to clinical science. Both organic and inorganic nanoparticles (NPs) have shown tolerability, pharmacologic specificity and biodegradability. A subclass of NPs, protein NPs, have garnered recent attention due to the inherent biocompatibility of protein substrates. Protein NPs are currently being employed widely in pharmaceuticals development with applications in nasal, pulmonary, intravenous, ocular and oral delivery. Despite the distinct advantages of orally administered pharmaceuticals, the development of oral delivery systems has been comparatively limited. Therefore, this review attempts to discuss the most recent experimental and pre-clinical findings in the development of protein NPs for oral delivery, while envisioning upcoming challenges.
Oral drug delivery of nanomedicine
2020, Theory and Applications of Nonparenteral Nanomedicines
Oral drug delivery is the most preferred administration route due to noninvasive, high patient compliance, convenient to handle, and does not require any specific sterile conditions. However, some of the drugs administered orally face several physical, biological, and biochemical barriers which lower the therapeutic efficacy of the drugs before getting absorbed into the systemic circulation. The utilization of nanocarriers for oral drug delivery overcome abovementioned barriers and considered as an alternative strategy to address the drawbacks of oral drug delivery. In this chapter, the recent advancement of nanocarriers in oral drug delivery application for the treatment of various diseases is summarized. Furthermore, the chapter explains how different nanocarriers designing technology enhance the therapeutic potential to overcome the various barriers such as physical, biological, and biochemical. Although, in recent years, several nanocarrier-based drug delivery technologies have been evolved and showing promising results but still it is far from the real utilization in the clinic.
Pharmacogenomics
2019, A Practice of Anesthesia for Infants and Children
Pharmacogenomics is a rapidly evolving and novel science that has the potential to revolutionize the way we deliver anesthesia and analgesia to pediatric and adult patients. It allows for personalization of drug delivery tailored to an individual’s genetics and their consequent influence on drug metabolism, exposure and effects. In this chapter, we present some historical perspectives and basics of pharmacogenomics. Early discoveries in this field are tied to anesthesia, such as cholinesterase deficiency and malignant hyperthermia. We discuss developmental pharmacogenetics with relevance especially for the youngest pediatric patients, and then extensively describe the role of genetic variants of the phase I and II liver enzymes on the pharmacokinetics of commonly used drugs in anesthesia and analgesia. Particular attention is devoted to the CYP2D6 genetic variants which have recent implications in opioid analgesia, leading to regulations for codeine use in children less than 18 years old. Genetics affecting drug effects (pharmacodynamics) and perioperative outcomes like postoperative nausea are also described. The goal of understanding genomics is clinical translation to improve patient outcomes; costs and insurance coverage of genetic tests, limitations of research studies and interpretations of results and patient implications are deterrents to this goal. By integrating genomic data into electronic health records, creation of decision support systems and empowering anesthesia providers with information about pharmacogenomics, implications, and availability of current online sources, precision medicine is potentially poised to make anesthesia delivery safer and more efficient, although this is still a work in progress.
Pharmacogenomics
2018, A Practice of Anesthesia for Infants and Children
Pharmacogenomics is a rapidly evolving and novel science that has the potential to revolutionize the way we deliver anesthesia and analgesia to pediatric and adult patients. It allows for personalization of drug delivery tailored to an individual’s genetics and their consequent influence on drug metabolism, exposure and effects. In this chapter, we present some historical perspectives and basics of pharmacogenomics. Early discoveries in this field are tied to anesthesia, such as cholinesterase deficiency and malignant hyperthermia. We discuss developmental pharmacogenetics with relevance especially for the youngest pediatric patients, and then extensively describe the role of genetic variants of the phase I and II liver enzymes on the pharmacokinetics of commonly used drugs in anesthesia and analgesia. Particular attention is devoted to the CYP2D6 genetic variants which have recent implications in opioid analgesia, leading to regulations for codeine use in children less than 18 years old. Genetics affecting drug effects (pharmacodynamics) and perioperative outcomes like postoperative nausea are also described. The goal of understanding genomics is clinical translation to improve patient outcomes; costs and insurance coverage of genetic tests, limitations of research studies and interpretations of results and patient implications are deterrents to this goal. By integrating genomic data into electronic health records, creation of decision support systems and empowering anesthesia providers with information about pharmacogenomics, implications, and availability of current online sources, precision medicine is potentially poised to make anesthesia delivery safer and more efficient, although this is still a work in progress.

View all citing articles on Scopus

View full text

Research ArticlesNasal administration of low molecular weight heparin

Abstract

Section snippets

INTRODUCTION

Materials

Nasal Absorption Studies

CONCLUSIONS

Acknowledgements

J Pharm Sci

Pharmacol Ther

J Am Coll Cardiol

Blood

J Pharm Sci

Nasal systemic drug delivery

Nasal delivery of peptides, factors affecting nasal absorption

Systemic delivery of peptides and proteins across absorptive mucosae

Crit Rev Ther Drug Carrier Sys

The biopharmaceutical aspects of nasal mucoadhesive drug delivery

J Pharm Pharmacol

Insulin delivery in nosedrops: New formulations containing alkylglycosides

Endocrinology