This action might not be possible to undo. Are you sure you want to continue?
By Dr.Shruti Bhat, Canada. Executive Pharmaceutical Applications SME, Macro2Micro,
About the author : www.Pharm-Education.com
Management of illness through medication has entered a new era in which an enormous number of biotechnology based products, peptides / proteins pharmaceuticals are available / synthesized for therapeutic use. The growing interest can be ascribed to the increased understanding of their role in physiology and therapy as well as the established capability of producing large quantities with consistent quality by the biotech route. As technological innovation spreads throughout medicine so does the "cutting edge" come to drug delivery systems alias „Mucoadhesive Drug Delivery‟.
Some examples of this system include, the BioErodible MucoAdhesive (BEMA) delivery system is designed to deliver either local or systemic levels of drugs across mucosal tissues. This delivery system offers rapid onset of action and improved drug bioavailability compared with the oral route. As an added benefit, drug inactivation by first-pass metabolism in the liver is avoided. The BEMA delivery system consists of a dime-sized disk with bioerodible layers that delivers drugs rapidly over specified time intervals. The erosion rate is controllable, and there is no residue to remove and so far has shown promise for the administration of pain medications, antiemetics, and antimigraine drugs (Clinical Trials, 2008, February).
One example of this technology is the BEMA Fentanyl mouth patch from BioDelivery Sciences International (Raleigh, NC), which is currently in phase III trials. It is designed to assist with breakthrough cancer pain for opioid-tolerant patients. Dr. James North, MD, principal investigator for the phase III efficacy study reports, "Breakthrough cancer pain can be devastating to patients with cancer and their families. Patients suffering from breakthrough cancer pain need treatment options that provide effective pain relief and are easy to administer" (Triangle Business Journal, 2009, May) .
Mucosal drug delivery technologies are expanding exponentially with applications in every imaginable route of administration because of the indisputable therapeutic benefit this delivery technology brings. Benefits include site-specific targeting, less frequent dosing, and maintaining effective plasma concentration without increased consumption
The global market for advanced drug delivery systems was more than € 37.9 billion in 2000 and is estimated to grow and cross € 95 B (i.e., controlled release €19.8B, needle-less injection € 0.8B, injectable /impantable polymer systems €5.4B, transdermal € 9.6B, transnasal €12.0B, pulmonary € 17.0B, transmucosal €4.9B, rectal €0.9B, liposomal drug delivery € 2.5B, cell/gene therapy € 3.8B, and balance covered by miscellaneous ). Table 1, mentions a brief list of representative peptide and protein drugs and their potential functions and biomedical applications.
Table 1 : List of representative peptide / protein drugs in bio-medical applications.
Peptide / Protein drugs Cardiovascular - active peptides & proteins- Angiotensin II antagonist - Antriopeptins
Functions / applications
- Lowering blood pressure. - Regulating CVS function & electrolyte & Fluid balance.
- Bradykinin - Calcitonin gene related factor - Captopril - Tissue plasminogen activator - Urokinase, streptokinase - Albumin, Plasma proteins 2 CNS active peptides & proteins- Cholecystokin (CCK-8 or CCK 32) - Delta sleep inducing peptide (DSIP) - B-endorphin - Melanocyte inhibiting factor I - Melacyte - stimulating hormone - Neuropeptide Y - Nerve growth factor 3 GI active peptides & proteins- Gastrin antagonist. - Neurotensin - Pancreatic enzymes - Somatostatin 4 Immuno modulating peptide & proteins- Bursin - Colony stimulating factor - Cyclosporine - Enkephalins - Interferon
- Improving peripheral circulation. - Vasodilator. - Heart failure arrangement. - Dissolution of blood clots. - Thrombolytic therapy. - Blood volume replacement.
- Suppressing appetite. - Improving sleep that is disturbed. - Relieving pain. - Improving the mood of depressed Patients. - Improving attention span. - Controlling feeding & drinking behavior. - Stimulating nerve growth & repair.
- Reducing secretion of gastric acid. - Inhibiting secretion of gastric juice. - Digestive supplement. - Reducing bleeding of gastric ulcers.
- Selective B-cell differentiating hormone. - Stimulating granulocyte differentiation. - Inhibiting functions of Flymphocytes. - Stimulating lymphocyte blastogeneis. - Enhancing activity of killer cells.
- Muramyl dipeptide
- Stimulating non-specific resistance to bacterial infections.
- Thymopoietin - Tumor neurosis factor
- Selective F cell differentiating hormone. - Controlling polymorpho nuclear Functions.
Calcitonin, oxytocin, corticotroptin, desmopressin, vasopressin, glucagon, tetracosactide
Acute or long term stimulation of endocrine axes.
Metabolism modulating peptides and Proteins- Human growth hormone - Gonadotrophins - treating hypopituitary dwarfism. - Inducing ovulation, spermatogenesis & cryptochialism. - Insulin - Leuteinizing hormone releasing hormone (LHRH) - Oxytocin - Thyrotropin releasing hormone (TRH) - Treating diabetes mellitus. - Inducing ovulation in women with hypothalamine amenorrhea. - Maintaining labor. - Prolonging infertility & lactation in women who are breast-feeding. - Vassopressin - Treating diabetes insipidus.
Miscellaneous - Adenosine deaminase - Dextranase - p Fructofuranosidase - Mannosidase - L Asparaginase - B Glucosidase - Thrombin like enzymes of snake venoms - Enzyme deficiency. - Lysosomal storage - Storage disease - Mannosidosis - Cancer - Adult Gauctier‟s disease - Thrombosis
The objective of this review article is to understand the opportunities available to delivery peptides and protein molecules as mucosal DDS and the complexities associated with the formulation thereof.
The development of delivery systems for therapeutic peptides and proteins and their evaluation depend on the biophysical, biochemical and physiological characteristics of the peptide molecules including their molecular size, bio half-life, immunogenicity, conformational stability, dose requirement, site & rate of administration, pharmacokinetics and pharmacodynamics. The immunogenic potential of any impurities or the peptide molecule itself must also be taken into consideration. Since, peptides are complex
structures and exhibit anomalous behavior (against conventional drug moieties) to environmental
conditions; the study of its chemistry, preparation, purification etc. before dosage form design (since these parameters affect its stability on shelf) becomes vital.
To begin with, let us first understand the chemistry and the complexities of peptides and formulation considerations of peptide based administration. therapies employing mucosal routes of
CHEMISTRY OF PEPTIDES:
Structural aspects of peptide based drugs: Peptide history predates to 1906 when Emil Fischer coined the name “peptide” to describe the products formed on linking amino acids via amide or peptide bonds. The term polypeptide refers to the peptides, which contain eight or more amino acids whereas oligopeptides are those, which have less than 8 amino acids. Polypeptides that contain from about 50-2500 amino acids are termed proteins. Proteins with 2 or more polypeptide chains are known as oligomeric proteins, their component chains are called subunits or protomers.
Current methods of peptide synthesis:
There are several techniques currently available for the synthesis of peptides and proteins. include: i. ii. iii. iv. v. Classical solution based methods. Solid phase methods. Enzyme methods. Semi-synthetic methods and Recombinant methods.
The routes of synthesis are not general and the choice of method depends upon the target molecule under investigation.
Purification of peptides:
There are many acceptable, well-practiced ways of purifying peptides to produce products suitable for administration by parenteral and/or other non-invasive routes. In other words, the peptides should be pyrogen free, non-antigenic and preferably sterile. Purification procedures are based on the individual characteristics of the target sequence and the type of impurities likely to be associated in the polypeptide molecule. The impurities basically originate from 2 quarters viz. Source derived impurities and Process derived impurities, mentioned in Table 2.
Table 2: Potential impurities associated with peptide-based molecules-
Impurities Source derived impurities - Proteins
Pharmacological irregularities product
- Immunity, hypersensitivity, adjuvant effects, unknown biological activity.
- Nucleic acids - Endotoxins - Agents of infection B Process derived impurities - Heavy metals & process chemicals - Coloumn materials - Pyrogens
- Oncognesis - Pyrexia - Disease or tumors
- Toxicity - Immunogenic reactions - Pyrexia
Characterization of peptides: Determination of a protein‟s amino acid sequence is often performed as a confirmation of the proteins structure, since the arrangement of sequence of amino acids in the protein largely characterizes the unique properties of these molecules particularly with respect to their biologic activity. That the
arrangement of amino acids can have a powerful effect upon the behavior of proteins molecules has been spectacularly demonstrated by the results of mutations that can cause as a result of deletion or change of a single amino acid. The best-known example of this property is probably the disease sicklecell anemia, caused by such a defect in hemoglobin synthesis. Another example of this structural identity of proteins is platelet derived growth factor with sis-oncogene, which provided insight into the molecular basis of tumorigenesis. Table 3, below enlists characteristics of some therapeutic peptides.
Table 3: Characteristics of few therapeutic peptides Dry substance Sandostatin Oxtyocin Vasopressin Desmopressin Glucagon Calcitonin Interferons Erythropoetin tPA Size 8 amino acids 9 amino acids 9 amino acids 9 amino acids 29 amino acids 33 amino acids 15-30 KDa 34 KDa 68 KDa Various structures some glycosylated Heavily glycosylated One or two chains glycosylated } } Cyclic nona peptides } Other characteristics
Immunoglobulins Factor VIII
150 KDa 330 KDa
4-chain structures Glycosylated
Protein micro sequencing can be performed by classical Edman degradation technique. Progressive protein micro sequencing has also been achieved using polyacrylamide gel electrophoresis, mass spectroscopy, electrochemical detection as well as Fast atom bombardment mass spectroscopy (FABMS). However, there is no single analytical technique that can be used in isolation to characterize a peptide unambiguously. The greater the number of analytical procedures to which a peptide product can be subjected, the more certain the user can be of its purity and authenticity.
As is the case with classical chemical substances, drug and diagnostic products that have their origin in biotechnology must meet standards that define their identity, strength, quality and purity. Although the basic requirements that apply to biotechnology products are the same as these that apply to classical chemical substances, the analytical methods that are required for evaluating the two types of materials and the considerations for their quality control are quite different.
Potency of Proteins:
Three very reliable techniques employed for peptide estimation include-
1. RIA 2. Chromatography. 3. Fast atom bombardment mass spectrometry.
Potency determinations for proteins can range from complex bioassays that often use cell culture procedures to enzyme immunoassays and radio immunoassays (RIA) as well as more classical methods of chromatography. Major attention must be given to quantitating the biological activity of the intact molecule as well as to determining whether the protein has been denatured or inactivated during the manufacturing process. Intact proteins can have a disturbed secondary or tertiary structure, which can render these proteins partially or completely inactive. The correlation of bioactivity with classical assay procedures much as HPLC or immunoassays should be adopted as a long term goal so that these more precise methods of assay can eventually replace tedious and less precise bioassay methods.
RIA techniques exploit the specific and tight association of antibody with a peptide / protein drug in a variety of complex matrices. The ability of a protein antigen to combine with its corresponding antibody
is a structurally and conformationally specific interaction. Thus, if the protein or the antibody were conformationally altered i.e. denatured, a less than optimal protein-antibody interaction would occur. A drop in the immunochemical assay does not necessarily imply a drop in bioactivity since the decomposition products or the conformationally altered protein may still be bioactive. On the other hand, decomposition of the protein may not be reflected in the immunochemical assay as long as the antigenic determinant part of the protein molecule is intact and capable of reacting with the antibody.
HPLC on the other hand was found to differentiate among the insulin from cows, pigs and men and to be both reproducible and stability indicating. For insulin and insulin injections subjected to accelerated stability tests, the HPLC method detects the decomposition that cannot be detected by either the mouse blood glucose assay or the immunoassay.
Table 4, compares the relative merits and demerits of chromatorgraphic and RIA analytical techniques in the analysis of petide / protein drugs.
Table 4: comparative merits and demerits of chromatorgraphic and RIA analytical techniques in the analysis of petide / protein drugs
Parameters Development time Specificity Matrix dependence Detection Short
Can be modified Adaptable Depends on intrinsic properties or derivation
Not easily changed Strong Independent of intrinsic character
Sensitivity Assay throughput Recovery during sampling preparation Validation
Good Relatively slow Internal standards
Better Generally fast Difficult at low concentration.
For low conc. may require LC/GC MS.
Fast atom bombardment mass spectrometry:
This technique is also very useful in peptide/protein analysis.
A radio receptor assay has been A method for
described for insulin. Enzyme assays also have very high specificity and sensitivity.
determining the particle size of zinc-insulin and its distribution in suspension formulations, based on the measurement of absorbance in the high UV-Visible region has been reported.
In view of the complex structure of proteins, the correlation of bioactivity with classical assay procedures such as HPLC or immunoassays should be adopted to gain a greater confidence in the data generated.
Toxicity and safety:
For proteins and polypeptides being developed as drugs, preclinical studies have two complementary aims:-
a. to demonstrate potential utility and b. To rule out useless or harmful compounds without efficiency and economical.
The tests include:
1. Efficacy testing:
The range of substances and potential action is so extensive that only a general account can be given of the principles underlying efficacy testing. The first need is to define the specific biological activity that is considered or believed to represent the mechanism of the therapeutic goal. This might be perceived as a change in a receptor or in an intracellular effector, a clear-cut biological response in cells, in vitro a more complex response in an animal. It is necessary to explore the principal effect of the candidate drug and the mechanism of that action in whatever test systems are available.
2. Toxicity testing:
This covers at least as broad an area of biological assessment of efficacy test. The need is to detect and characterize potentially harmful actions in such a way that an informed judgment can eventually be made between the likely therapeutic benefit and risk of treatment in deciding whether and how to undertake clinical trials or to apply for a product license.
3. Programme of toxicity testing:
The tests included are: general pharmacology, acute toxicity, pharmacokinetics, 2-4 weeks repeat dose toxicity test in one or two species, local irritancy, antibody formation, second species multi-dose test, complete kinetics and metabolism, mutagenecity, reproduction toxicity, pharmacodynamics, endocrine effects, state of immune system and metabolism toxicity.
Pyrogen and bacterial endotoxins are detected by the conventional rabbit test, LAL testing or pyrogen evoked depression of plasma testing.
Since, peptides are highly potent, their delivery systems must be extremely precise in the rate of delivery. Furthermore, the delivery pattern must be properly designed to suit the pattern and
mechanisms of the pharmacological action of the therapeutic peptides and proteins to be delivered. Also, the peptide therapy generally is chronic. Moreover, the rapid disappearance of most peptides from body owing to their degradation by proteolytic enzymes mandates implementation of a therapeutic regimen that requires multiple daily injections to maintain therapeutic efficacy. With high bioavailability reportedly achieved by parenteral administration, needle phobia a difficult parameter to monitor in the clinical setting, pharmaco economics and best clinical practitioners are progressing towards user friendly, effective and non-invasive mucosal drug delivery presentations of medicinal compounds. Because of this, the commercial success of using peptides and proteins as drugs depends on the development of new routes and methodologies for effective administration of these moieties.
The rapid growth in the development of peptide and protein therapeutics over the past decade has presented many formidable challenges to pharmaceutical industry. The early problems of bulk protein production, purification and analytical method development have largely become manageable. What remains, however is one of the most difficult challenges the development of alternate delivery routes for these macromolecular drugs.
Unlike most low molecular weight organic drugs where oral administration is feasible, the delivery of peptides and proteins by oral route is not yet possible. Due to their instability in the gastro intestinal tract and their high degree of hydrophilicity, proteins and peptides are delivered almost exclusively by the parenteral route of administration. There are many disadvantages to chronic injectable therapies. Chief among these are limited patient compliance, minimal pharmacokinetic control and tissue necrosis. In order to increase the therapeutic acceptance and competitiveness of protein therapies, non-invasive modes of administration are needed. Major efforts are underway to explore transdermal, oral, pulmonary and nasal delivery of protein and peptides in therapeutics.
The present article focuses on the potential routes of peptide delivery, their advantages, limitations and feasibility of use.
POTENTIAL ROUTES FOR MUCOSAL DELIVERY OF PEPTIDE PHARMACEUTICALS-
Muco (Bio) adhesion may be defined as the state in which two materials, at least one of which is of a biological nature, are held together for extended periods of time by interfacial forces. For drug delivery purposes, the term Bioadhesion implies attachment of a drug carrier system to a specific biological
location. The biological surface can be epithelial tissues, or the mucous coat on the surface of a tissue. If adhesive attachment is to a mucous coat, the phenomenon is referred as mucoadhesion. The mucosal layer lines a number of the body including the gastrointestinal tract, the urogenital tract, the ear, nose and eye.
These represent potential sites for the attachment of any bioadhesive system and hence, the mucoadhesive drug delivery system includes the following:
Buccal Delivery System Oral Delivery System Vaginal Delivery System Rectal Delivery System Nasal Delivery System Pulmonary Delivery system Colon targeted Delivery system Ocular Delivery System
The most recent being use of nano-technology in the development of mucosal DDS.
Nanotechnology in mucosal DDS: A new generation of drug delivery systems is being created as a result of the ability to design nano particles and their matrixes. Nano particles are very small molecules with a diameter of 1 to 100 nm. Drugs can be coupled to or encapsulated within these specialized molecules. Advantages of using nano particles as drug delivery systems include increased drug bioavailability and precise delivery of therapeutic agents to target organs, tissues, and cells (Leary, Liu, & Apuzzo, 2006). "Presently only 1 of 100,000 molecules of therapeutic intravenous drug reaches its desired destination. As a result of this, clinicians are faced with deciding whether to increase the drug dosage, which can lead to side effects, or reduce the dosage, which can limit the therapeutic effect" (Bulletin Board, 2008). Valuable clinical breakthroughs in using nanotechnology have already occurred in the areas of oncology, cardiovascular medicine, neurology, and orthopedics.
On the horizon are nano particles made of biodegradable and biocompatible mesoporous silicon particles designed to efficiently carry therapeutic agents to their intended site by successfully penetrating the body's immune system. These multistage nanoparticle systems deliver therapeutic agents in a manner similar to a space rocket launching from Earth through our atmosphere, in that the multilayered nanoparticle disposes of its outer layer as it moves through the body. Each layer of the nanoparticle is designed to efficiently meet and overcome each physiologic barrier that it encounters as it moves through the body. As a result, the multistage nanoparticle drug delivery system is able to successfully carry therapeutic agents to the intended site with greater efficiency and reduce the need for a higher
drug dose. As an added advantage, by successfully limiting drug side effects, it is hoped that greater patient drug adherence will result (Tasciotti, Liu, & Bhavane, 2008).
Nanoshells are another exciting development in drug delivery. These molecules are hollow silica spheres covered with silver, gold, or other metals that can be chemically equipped to carry antibodies. This technology allows the nanoshell to successfully attach to specific cells within the body and deliver their payload. By precisely delivering medication to the intended site, systemic side effects can be minimized (Leary et al., 2006). Drugs may also be encapsulated within the metal nanoshells. The healthcare provider of the future will have the ability to trigger the nanoshell with an external force to release its therapeutic agent at the precise time that it reaches its intended target within the body. Infrared light and magnetic fields are currently being explored as possible triggers. This drug delivery system is expected to be especially useful in the area of oncology for the treatment of tumors because high concentrations of therapeutic agents can be delivered to the tumor, and the toxic effects to surrounding tissues can be minimized (Yih & Al-Fandi, 2006; Hafeli, 2004).
Drug-loaded erythrocytes are another nanotechnology drug delivery system under development. Erythrocytes are split open and loaded with the desired therapeutic agent. Using nanotechnology, the surface of the erythrocyte is enhanced with glutaraldehyde, antibodies, or specific carbohydrates, which increase the erythrocytes' circulation half-life, allowing for body barrier penetration and precise drug delivery. Once delivered into the patient's body, the erythrocytes circulate in the blood and reticuloendothelial systems and slowly release the intended agent (Hirlekar, Patel, & Dand, 2008).
A vaccine carrier system using nanoemulsions is currently being researched. This medication delivery system uses nanotechnology to vaccinate against HIV. There is recent evidence that HIV can infect the mucosal immune system. Therefore, developing mucosal immunity through the use of nanoemulsions may become very important in the future fight against HIV (Bielinska, Janxzak, & Landers, 2008). The oil-based emulsion is administered in the nose, as opposed to traditional vaccine routes. Research is demonstrating that genital mucosa immunity may be attained with vaccines that are administered into the nasal mucosa.
Engineered nanotechnology molecules have demonstrated superior performance over present-day monovalent drug delivery systems that have only one site of attachment. A special architectural class of nano particles called dendrimers consists of a central core with many branches that allow molecules to attach to its surface (Morrow, Bawa, & Wei, 2007). Dendrimers in research have been fashioned into sophisticated anticancer machines carrying five chemical tools: one to bind to cancer cells, a second that will fluoresce upon locating genetic mutations, a third that assists in imaging the tumor shape with xrays, another that carries drugs to be released on demand, and one that sends a signal when cancerous
cells are dead. Additionally, in the future, dendrimers may be used to place genes in cells. It is also hypothesized that nanotechnology could be used to design specially engineered cardiomyocytes to repair damaged hearts and erythrocytes capable of delivering much higher levels of oxygen to tissues (Morrow et al., 2007).
Precise therapy parameters in the future may be maintained with implantable drug delivery and biosensing microchips. These "intelligent" systems will provide real-time therapeutic monitoring and control the time, amount, rate, and location of drug delivery. The microchip devices will contain an array of individually sealed and actuated reservoirs. The passage of a threshold level of electric current through the device will cause it to disintegrate, exposing the drugs in the reservoir to the surrounding environment (Maloney, Uhland, & Polito, 2005).
In the area of neuroscience, biosensor technology is already being used to monitor glutamate levels at the surface of living cells to provide information on the neurological damage occurring in stroke and neurodegenerative disorders and to detect the early formation of amyloid-[beta] protein found in Alzheimer‟s disease "Nanomachines that could move through the body troubleshooting and repairing tiny brain or cardiovascular lesions lie in the future" (Morrow et al, 2007).
Another system, the NanoStat platform technology enables both topical anti-infective products as well as a broad range of mucosal vaccines. The technology employs high-energy, oil-in-water emulsions that are manufactured at a size of 150-400 nanometers and are stabilized by surfactants. The unique aspect of products derived from the company's NanoStat technology is that, unlike currently available therapies, NanoBio's treatments are selectively toxic to microbes while non-irritating to skin and mucous membranes. The NanoStat technology also enables a platform of nanoemulsion based mucosal vaccines. When either whole virus or a recombinant protein antigen is simply mixed with nanoemulsion and placed on the naso-pharynx, the nanoemulsion serves as a potent adjuvant, producing both mucosal immunity and systemic
Nanotechnology is not yet here for daily use, free, additional information on Nano Technology may be found in my presentation entitled „ Nano Technology or magic bullet in medical science?‟‟ on linkedin. Interested readers could also contact me on my blog www.Pharm-Education.com
Other new methods of peptide drug delivery continue to come to market, such as intranasal medications, pain balls, pulmonary deliver, trans-git etc.
Choosing the lungs to deliver drugs beyond airways is not new. Nicotine and other anesthetics have been delivered to the blood stream this way for many years. However, the high surface area for
absorption, the low level of enzymatic activity, the high physiologic pH together with rapid onset of drug action are key reasons why lung is a good site of delivery for peptides and proteins. It is particularly good for those, which have short half-lives. The key to delivering peptides & proteins to lungs is to target the small airways where the endothelial cells are directly connected with the alveolar endothelium. To deliver drugs deep into the lungs require particles of a precise size and a device, which delivers the drug regardless of a patient‟s breathing patterns. Delivering drugs by inhalation requires precision engineering for optimum results.
Inhalation devices- an engineering overview Today‟s inhalation devices have many design criteria, which they must meet. Not only is it important that they deliver the drug in the correct form, to the correct target site they must also offer the patient ease of use, guarantee repeatable performance and low cost and all of which should be coupled to aesthetic appeal and social acceptability.
The large number of devices currently available can be amalgamated into 3 groups broadly, nebulisers, metered dose inhalers (MDIs) and dry powder inhalers (DPIs). For each, the basic operating principles, advantages and drawbacks will be reviewed followed by a consideration of possible enhancements and the future for devices in general.
Nebulisers could mostly be described as devices for generating aerosols using an external energy source to achieve atomization. Commercially, there are two basic systems available grouped by the energy source used, air jet nebulisers wherein a stream of high velocity air (dry and clean) is passed over a source of liquid (water) containing the drug. The resulting negative pressure causes the liquid to be drawn into the air stream from the reservoir. The air flow rate, the rate of which liquid is drawn into the stream and to a certain extent the surface tension of the liquid determine the initial droplet size. The stream may then be impacted into a baffle system of plates and filters, which refines the aerosol by removing the large droplets and releasing an aerosol, which is closer to being mono-dispersed at the target size. Typically for air jet nebulisers, this is in the range of 2-4 m.
Ultrasonic nebulisers are the high frequency vibrations of piezo electric crystals to impart kinetic energy to the liquid; some of this energy in turn is used to create new surface area in the liquid, which will assume the most stable form of spherical droplets, due to its surface tension. These new droplets of liquid retain some of the imparted kinetic energy, which throws them clear of the bulk liquid, forming an aerosol in the nebuliser.
Both types of nebulisers can produce similar size distributions of aerosol, the ultrasonic systems having the advantage that they can nebulise relatively large volumes of liquid, without the associated high airflow requirement and resultant evaporative losses. Metered dose inhalers (MDI)-
Metered dose inhalers (MDIs) can be viewed as a number of individual interactive components- the valve, the propellant & the inhaler (activator). The propellant systems normally used consist of a cocktail of one or more chloro-fluorocarbon (CFC). These compounds possess properties, which make them difficult to replace easily, such as volatility, low toxicity and low flammability. Because these propellants possess a distinct equilibrium vapor pressure at a given temperature in a closed MDI system that pressure is acting throughout the system and is effectively constant through the life of the pack, as long as liquid propellant remains (excluding preferential evaporation).
The portability, close consistency, accurate targeting, low cost and discrete use of MDIs mean that in terms of total numbers, they are the most frequently prescribed form of inhalation device. Unfortunately there are 2 main disadvantages. The first of these has developed in recent years, in as much as MDI are no longer considered environmentally acceptable (an issue which is beyond the scope of this article) due to the use of chlorofluro carbon propellants. The second disadvantage is a more long-standing problem and is one of misuse, patient in co-ordination and cold cough syndrome. Breath actuated inhalers (BAIs) and inhalers with spacer chamber offer solution to the problems.
Dry powder inhalers-
Dry powder inhalers (DPIs) are breath-actuated devices, by virtue of the fact that the kinetic energy imparted to the drug comes from the patient inhaling. The basic construction of all DPIs consists of mouthpiece and a turbulence chamber for dispersing the drug into the air stream. To reduce the incidence of agglomeration, the active material is normally loosely bound to a longer carrier such as lactose. A metered dose of the drug is introduced into the chamber from its storage area, which can be bulk, capsules or blister form. The patient then inhales and the resulting turbulence possibly assisted by mechanical agitation disperses the powder into the air stream and separates the drug from the carrier. Continued inhalation carries the drug into the airways where deposition occurs. Because of design constraints in order to achieve optimum dispersion, airflow rates through the device have to be relatively high = 60 L/min. Because of high air flows mean and high flow velocities, the inertia of the particles is higher and the resulting deposition in the upper airways in higher.
This area is probably best reviewed by considering the possible developments within each group.
Intrapulmonary and Endotracheal Routes of Administration
According to current guidelines recommended for the management of cardiac arrest, the American Heart Association has recommended that when intravenous or intraosseous routes cannot be established, endotracheal administration of some resuscitation drugs be used. Medications that can be absorbed through the trachea include lidocaine, epinephrine, atropine, naloxone, and vasopressin (American Heart Association [AHA], 2005). Although the optimal dose of these drugs has yet to be established, two to two and one half times the recommended intravenous dose is used (AHA, 2005). Recent studies investigated the intrapulmonary route of drug administration. One study suggests that intrapulmonary vancomycin may have efficacy in acute lung injuries, such as meconium aspiration syndrome in neonates (Jeng, Lee, & Soong, 2007). Televancin is also being studied for intrapulmonary use. Because the antibacterial activity is not affected by pulmonary surfactant, further studies of intrapulmonary televancin for use in treating gram-positive respiratory infections are underway (Gotfried et al., 2008).
Nebulisers, by virtue of their design and their need for an external energy source, tend in the main to be bulky and expensive and because of longer treatment period come low on social acceptability scale. Work in this area is likely to be directed towards smaller, most compact, low cost units suitable for home use. Metered dose inhalers represent a field in which developments are currently taking place. Continued interest is being shown in innovations on BAIs and spacer chamber based MDI. Dry powder inhalers will continue to appear in the market place in new and improved forms, the main areas of improvement being in the airflow/dispension chambers and the drug storage systems, the main objective being ease of use.
INTRANASAL ADMINISTRATION FOR PROTEINS & PEPTIDES-
Due to its unique physiology and ready accessibility, the nasal cavity is an attractive delivery site for the systemic administration of therapeutics. The nasal membrane or mucosa lines the nasal cavity and is located posterior to the external nares. The surface area of the nasal mucosa is relatively large (180 cm ) and has a rich blood supply (40ml/min/100g). Molecules absorbed across the mucosal membranes are transported directly to the blood stream and therefore avoid clearance due to first pass metabolism. Also, the protease activity in the nasal cavity is greatly diminished relative to the small intestine making enzymatic degradation in the nasal cavity less likely. Relative to chronic parenteral administration, intranasal delivery offers increased patient compliance and in some cases, increased pharmacokinetic control.
Intranasal formulation is a remarkable and easy mode of drug delivery. It is a needle-free, patientfriendly route that does not contribute to biohazardous waste (Wermeling, Miller, & Rudy, n.d.). Pharmacokinetically, the absorption rate is so rapid that it results in a faster onset of action compared with oral and intramuscular administration. In addition, hepatic first-pass metabolism is avoided (Wermeling et al., n.d.). (The metabolism of an administered dose of a drug by the liver before it reaches systemic circulation is referred to as the first-pass metabolism.) For many oral drugs, a clinically
significant portion of the drug taken is destroyed during first-pass metabolism, requiring a higher oral dose for a given effect (Wynne, Woo, & Olyaei, 2007). Intranasal drugs can be delivered in a variety of formulations that include powders, drops, topical gels, and sprays. Consideration must be given to normal physiologic processes when using the intranasal route, as the nose is an important defense system for environmental hazards. Any disruption of its normal physiology may leave the patient vulnerable to a variety of complications (Wermeling et al., n.d.). The delivery devices for intranasal medications can be costly, as illustrated by intranasal insulin, and can be a deterrent to patient use. Initially thought to be a desired route compared with subcutaneous insulin, patients found intranasal insulin to be burdensome and costly (R. Talbert, personal communication, February 21, 2008). Until recently, vitamin B 12 has been available only by intramuscular injection. Calomist (cyanocobalarain) Nasal Spray is now available in a 25-mg/spray form that is used daily in lieu of the monthly injections. This can now be included in the daily routine with less impact of a missed dose.
Medication Adherence : Medication adherence can be problematic with older adults. One of the most basic forms of medication delivery, the pillbox, is continually being updated. An interactive pillbox can be a useful tool in reminding this population about their medication times. Pillboxes are available that can hold as much as a 1-month supply of medications, with separate compartments for as many as four drugs. After programming, the box will beep at the time a medication is due to be taken, indicate the appropriate compartment, and display the number of pills to take. When the compartment lid is lifted, an audio message instructs the patient on the number of pills to take, along with specific information about how that medication should be taken. The data are gathered and can be transmitted via phone lines to the caregiver to confirm the time at which the medication was taken. Even patients thought to be compliant accidentally skip doses of medication, a silent problem improved by these devices. Pillboxes with multiple compartments are particularly helpful for older patients when dealing with multiple pill regimens.
The intranasal administration of small organic compound is a well-established mode of delivery. The majority of these drugs however, are intended for local administration to the nasal mucosa rather than systemic administration. Current nasal products marketed in the USA & a selected list of products of European products are shown. in Table 5.
Table 5- Currently marketed nasal products.
Product Topical administration 1. Beconase Nasal spray
2. 3. 4. 5. 6. 7. 8.
Decadron Phosphate Turbinaire Dristan Nasal spray Nasal crom Nasal solution Nasalide Nasal solution Otrivin Nasal spray Privine Nasal spray Vancenase Nasal spray Systemic administration
Dexamethasone phosphate Oxymetazoline HCl Cromolyn sodium Flunisolide Xylo metazoline HCl Naphazoline Beclomethasone dipropionate
1. 2. 3. 4. 5.
DDAVP Diaprid Nasal spray Syntocinon Nasal spray Calcitonin Sandoz Nasal spray 50 (Europe) Suprefact Nasal spray (Europe)
Desmopressin acetate Lypressin Oxytocin Salmon calcitonin Buserelin
All of the nasal products listed in the above table intended for systemic administration are peptides. This is reflection of both the lack of alternatives to parenteral administration as well as the advantages of nasal administration for peptides. Unfortunately, not all peptides and protein therapeutics can be delivered systematically with good bioavailability by the intra-nasal route.
The following are few factors affecting nasal absorption-
Drug effectMolecular size. Lipophilic hydrophilic balance. Enzymatic degradation in nasal cavity.
Nasal effectMembrane permeability (interspecies differences) Environmental pH. Mucociliary clearance. Colds, rhinitis.
Delivery effectFormulation (concentration, pH, Osmolality) Delivery systems (spray, drops, powder) Deposition. Formulation effects in mucociliary clearance. Toxic effects on ciliary function and epithelial membranes.
Table 6 mentions bioavailabilities of various peptides and proteins are shown as a function of the number of amino acids.
Table 6: Nasal bioavailability and molecular weights of some peptide and protein drugs.
Compound TRH Somastatin analogue Metkephamid Oxytocin Desmopressin Buserelin LHRH Nafarelin ACTH analogue Secretin Glucagon Calcitonin Insulin Beta interferon Growth hormone
# Amino acids 3 6 5 9 9 9 10 10 17 27 29 32 51 165 191
% Bioavailability 45 75 100 1 10 2.5 1.5 2 12 10 <1 <1 <1 <1 <1
Even though these values have been collected from a variety of sources, using varying techniques and different animal models, the trend is clear: Bioavailability drops sharply as the molecular weight increases. As long as the therapeutic indices are high and the cost of goods are low, therapeutic formulations of peptides for nasal administration can be feasible despite a low bioavailability.
Pharmacology & Toxicological considerations-
The safety of any delivery technology must be rigorously evaluated before it can be considered as a viable delivery alternative. The assessment should occur individually with both the delivery system and in combination with the active component. This is especially for trans-nasal delivery systems, which will be used systemically. For a nasal product which contains an excipient, that affects nasal permeability, the systemic topical effects of the excipients as well as individual peptide be evaluated. Mucociliary transport rate, patho/histo morphology and ciliary beat frequency tests are the commonly prescribed test for formulations delivered by nasal route.
BUCCAL DELIVERY OF PEPTIDES-
The presence of a smooth and relatively immobile surface for placement of a bioadhesive dosage form, the buccal region appears to be more suitable for continuous delivery of therapeutic agents using a bioadhesive system.
Since there is a limit to the size of the bioadhesive dosage form, only a limited amount of drug can be used in these systems. In general, any drug with a daily requirement of 25 mg or less is suitable for buccal delivery. Drugs with short biologic half lives requiring a sustained effect and exhibiting poor permeability, sensitivity to enzyme degradation viz. peptides may be successfully delivered via. oral transmucosal (OTM) delivery.
Generally small peptides with a probe tripeptide with a molecular mass of 670Da can be successfully delivered by buccal route. Captopril, oxytocin, chymotrypsin are some of the model drugs being investigated for possible delivery by this route.
The following mathematical equations may be used to predict transfer of drug buccally-
-dA / dt = (K1 RA ) / V dB / dt = (K1 RA) / V where, A and B = percentage of drug in the respective compartment; K= rate constant governing the transfer of unionized drug molecules between compartments (ml/min); R = fraction of drug unionized at any time „t‟; V = volume of the buffer in the oral cavity at time „t‟.
Relevant bioadhesive dosage forms in the buccal cavity include tablets, adhesive gels, adhesive patches and adhesive ointments.
Mucoadhesive gastrointestinal membrane The original concept of bioadhesive polymers as platforms for oral controlled drug delivery was to use these polymers to control and to prolong the GI transit of oral controlled delivery systems for all kinds of drugs. Several in vitro and ex vivo methods to test the bioadhesive properties of polymers and/or of coated microparticles have been described. Whereas bioadhesion has found interesting applications for other routes of administration (buccal, nasal, rectal and vaginal), it now seems that the controlling approach of GI transit has been abandoned before having shown any significant clinical outcome. According to in vivo results obtained in animals and in humans, it does not seem that mucoadhesive polymers are able to control and slow down significantly the GI transit of solid delivery systems. Attention
should be paid to possible occurrence of local ulcerous side effects due to the intimate contact of the system with mucosa for prolonged periods of time. As an example, oesophageal lodgement is known to be a potential cause of drug-induced injuries that can range from local irritation to perforation, depending on the ulcerogenic properties of the drug.
It is known that, the surface epithelium of the stomach and intestine retains its integrity throughout the course of its lifetime, even though it is constantly exposed to a high concentration of hydrochloric acid (as high as 0.16 N) and powerful protein splitting enzymes, like pepsin. This self-protective mechanism is due to the fact that, the specialized goblet cells located in the stomach, duodenum and transverse colon continuously secrete a large amount of mucous that remains closely applied to the surface epithelium. The mucus contains mucin, an oligosaccharide chain with terminal sialic acid (pKa= 2.6), which is capable of neutralizing the hydrochloric acid and withstanding the action of pepsin and thus protects the epithelial cell membrane.
The surface epithelium adhesive properties of mucin have been found out and recently applied to the development of gastrointestinal drug delivery devices based on bio (muco) adhesive polymers.
The concept of using mucoadhesive polymer to extend the GI transit time is elaborated in the figure 1. The drug delivery system coated with mucoadhesive polymer binds to the mucin molecules in the mucus lining and is therefore retained on the surface epithelium for extended periods of time. The drug molecules contained in the drug delivery device coated with mucoadhesive polymer are constantly released for absorption.
Fig.1 : Interaction of Mucoadhesive Drug Delivery System with Mucus Layer on Gastrointestinal Surface Epithelium
A bio (muco) adhesive polymer is a natural or a synthetic polymer capable of producing an adhesive interaction with a biological membrane, which is then called a bioadhesive polymer, or with the mucus lining on the GI mucosal membrane, which is thus called a mucoadhesive polymer. A bio (muco) adhesive polymer is known to have the following molecular characteristics: It has molecular flexibility; It contains hydrophilic functional groups; It poses a specific molecular weight, chain length and conformance.
The different types of polymers used in the mucoadhesive drug delivery system are: Carboxy methyl cellulose Carbopol Polycarbophil Tragacanth Sodium alginate Hydroxyl propyl methyl cellulose Gelatine Pectin Acacia Povidone
Details of excipients and parameters affecting product development shall be discussed under „formulation considerations‟ part II of this article.
OPTHALMIC DELIVERY OF PEPTIDES-
Ocular delivery of drugs is typically for the treatment of ocular inflammation, corneal wounds and glaucoma. This route has also been investigated for the systemic delivery of peptides and protein drugs. Mentioned below are few peptides being investigated for ophthalmic delivery.
Examples of peptides and proteins that is potentially useful in ophthalmology.
Peptides and proteins that may affect aqueous humor dynamicsA trial nutriuretic factor Calcitonin gene related factor LHRH Neurotensin Vasoactive intestinal peptide Vasopressin
Peptides and proteins that have immunomodulatory propertiesCyclosporine Interferon
Peptides and proteins that is associated with inflammationSubstance P
Peptides and proteins that affect wound healingEpidermal growth factor. Eye derived growth factor. Fibronectin Insulin like growth factor Mesodermal growth factor
Topical ocular drug delivery using conventional dosage forms such as solutions, suspensions and ointments is relatively inefficient with less than 10% of an applied dose being delivered across the cornea into the eye. Besides diffusion barriers the enzymatic barriers also play a very important role.
Contact lens sustained-release drug delivery systems are currently under investigation. Ocular drug bioavailability is known to be very poor. It is estimated that 95% of medication delivered by eye drops is lost as the medication mixes with tears and drains into the nasal canal (in-Pharma Technologist.corn, 2005, January). This medication delivery method is wasteful and can lead to unwanted local and systemic side effects. New drug delivery systems are being developed using polymers in contact lens, which hold therapeutic agents within their matrices to increase drug bioavailability to the eye. As the contact lens comes in contact with the eye, channels open that permit sustained drug delivery (Young, 2004). Researchers in Singapore have developed a new contact lens ophthalmic drug delivery system that has the ability to control the flow of drug by varying the width of the channels. In this manner, the drug delivery rate can be controlled and the drug remains effective for longer periods. Because the lenses are made in a one-step process, cost of manufacture is kept low. Potential applications include medication delivery for a range of eye diseases, including glaucoma, a leading cause of blindness that is currently difficult to treat, and loading wound-healing drugs in the lenses to treat corneal wounds. The lens material can also be modified to produce self-lubricating contact lenses to relieve the discomfort of contact lens wearers suffering from dry eyes (Alvarez-Lozano, Hiratani, & Concheiro, 2006; in-Pharma Technologist, 2005).
The transport of administered peptides and protein drugs across ocular barriers is mainly limited by proteinases such as neutral protease and aminopeptidase.
Despite the feasibility of systemic absorption of peptides from topically applied ophthalmic solutions, the ophthalmic route of peptide delivery is unlikely to be accepted -at least at the present. This is primarily
because of the innate aversion to instilling drugs into the eye and because of the perceived sensitivity of the eye, notably the corneal epithelium, to external insult such as when penetration enhancers are included in a formulation to promote absorption of peptides.
RECTAL DELIVERY OF PEPTIDES-
Rectal delivery of peptides and protein drugs is another very active area of research. Rectal delivery offers many advantages including-
1. Avoidance of drug absorption prior to reaching the systemic circulation and of drug contact with digestive fluids and consequential degradation. 2. The rate of drug absorption via. the rectum is not influenced by ingestion of food or the rate of gastric emptying. 3. Reduction in first - pass metabolism. 4. Rapid systemic absorption by administering the drug rectally in a suitable solution form. 5. Safe and convenient especially for infants and children. 6. Drug absorption can be interrupted in case of accidental overdose or drug reaction.
1. Factors affecting drug availability rectally-
1. Rectal fluid2. Amount 3. Composition 4. pH 5. Buffer capacity 6. Surface tension 7. Viscosity 8. Luminal pressure
2. Drug substance-
1. Solubility 2. Surface properties 3. Particle size 4. Drug concentration 5. pKa
3. Vehicle1. Composition 2. Fusion behavior
3. Surface tension 4. Rheological behavior.
The extent of breakdown of peptides is low in the lower digestive tract relative to the small intestine and the stomach, due to low enzymatic activity and neutral pH. Reports on peptide and protein drugs delivered by the rectal route include insulin, calcitonin, gastrin, pentagastrin, human growth hormone and vassopressin.
COLON TARGETING/ DELIVERY OF PEPTIDES-
The enzymatic activities associated with the micro flora of colon can be used as a tool for colon specific drug delivery. The large intestine has been appreciated as a promising site for the administration of poorly absorbable drug molecules for their improved bioavailability following oral administration. The colon is known to have somewhat lesser diversity and intensity of enzymatic activities as compared to stomach and small intestine. In addition, the colon has a longer retention time and appears to be highly responsive to agents that enhance the absorption of poorly absorbed drugs.
The site-specific delivery of drugs to the colon has implications in a number of areas which include1. Local treatment and irradication of colonic diseases. 2. For delivering peptides and proteins through oral route (colon targeted products). 3. In the improvement of therapy in diseases susceptible to diurnal rhythm.
Colonic delivery system-
The system designed for the delivery of drug in the colon may be of single or a multiple unit dosage form, which is based on the core being coated with one or more successive layers. Such a system may be composed of the following-
1. An outer film, which recognizes if the system has left the stomach. 2. An intermediate layer which swells (based on hydrophilic swellable polymer) following the outer film, which dissolves in the small intestine. This layer has to protect the core during the small intestine transit (at least 3-4 hours). 3. An additional layer between the swellable polymer and core is casted in order to deter premature release of contents.
The core containing the drug which may be released promptly or in a sustained/ prolonged pattern.
Factors affecting drug absorption from the colon-
1. Delivery rate to colon 2. Lipid solubility 3. Colonic residence, site of absorption in colon (proximal or distal) 4. pH / pKa of drug 5. Micro flora climate of colon 6. Mucous barrier 7. Mucosal pore size and permeability index 8. Concentration of drug Vs colon contents
In vitro models to assess colonic biotransformation-
To understand colonic drug disposition in vivo, following in vitro models are devised-
1. Studies with colonic tissues including colonic slices, segments, isolated mucosa, human colonic organ culture. 2. Studies with cellular preparations 3. Studies with sub cellular preparations viz. using coenzyme, cell fractionation isolate mitochondria and studying metabolism kinetics.
Methods of studying colonic drug absorption-
1. Radiolabeling: gamma scintigraphy or neutron activation analysis. 2. Gamma camera imaging. 3. Telemeric capsule. 4. Colonoscopy. 5. Artificial stroma.
For additional information on mucosal DDS, the following list of references may be present may be referred.
1. Brahmankar D. M., Jaiswal S. B. Controlled Release Medication in Biopharmaceutics and Pharmacokinetics a Treatise. 1 edition, Vallabh Prakashan, Delhi, 1995; 335-371.
2. Lachman Leon, Lieberman H. A., Kanig J. L.The Theory and Practice of Industrial Pharmacy.3 Edition, Varghese Publishing House, Bombay, 1987; 430-456.
3. Shruti Bhat, review article, Chemical Industry News, October 1998, p 1027. 4. Shruti Bhat, review article, Chemical Industry News, March 1998, p 275.
5. Chien Y. W. Novel drug Delivery Systems. Marcel Dekker, 1982; 171-177.
6. A J Moës.Gastric retention system for oral drug delivery. Drug Delivery Oral.2005. http://www.bbriefings.com/pdf/890/PT04_moes.pdf.
7. Jian-Hwa Guo, PhD ,Carbopol polymers for pharmaceutical drug delivery applications. Excipient Updates. Drug Delivery Technology.http://www.drugdeliverytech.com/cgi-
8. Seham S. Abd E Hady, Nahed D. Mortada, Gehanne A. S. Awad, Noha M. Zaki, Ragia A. Taha. Development of in situ gelling and mucoadhesive mebeverine hydrochloride solution for rectal administration. Saudi Pharmaceutical Journal. 2003; 11(4):159-171. 9. Khalid U. Shah, PhD & Jose G. Rocca, PhD. Lectins as next generation mucoadhesive for specific targeting of the gastrointestinal tract. Gastrointestinal Targeting, Drug Delivery Technology. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=245.
10. Kok Khiang Peh, Choy Fun Wong. Polymeric films as vehicle for buccal delivery: Swelling, mechanical and bioadhesive properties. Journal of Pharmacy and Pharmaceutical Sciences. 1999; 2(2):53-61.
11. Kashappa Goud, H. Desai, and T.M. Pramod Kumar.Preparation and evaluation of a novel buccal adhesive system.AAPS PharmSciTech. 2004; 5(3):article 35.
12. Joe McDonough and Wade Schlameus. Uncontrolled growth of controlled release drug delivery technology and markets. Pharmaceutical Research and Microencapsulation Specialists at the Southwest Research Institute.
13. Costas Kaparissides, Sofia Alexandridou, Katerina Kotti and Sotira Chaitidou.Recent advances in novel drug delivery systems. Azojono Journal Of Nanotechnology.2006; 10:2240/1110.
14. Woodley, John .Bioadhesion: New Possibilities for Drug Administration. Leading Article.Clinical Pharmacokinetics. 2001; 40(2):77-84.
15. Juan Manuel Llabot, Ruben Hilario Manzo and Daniel Alberto Allemandi. Double-layered mucoadhesive tablets containing nystatin. AAPS PharmSciTech 2002; 3 (3) article 22
16. K.P.R. Chowdary and Y. Srinivasa Rao .Design and in vitro and in vivo evaluation of mucoadhesive microcapsulesof glipizide for oral controlled release: a technical note. AAPS PharmSciTech 2003; 4 (3) Article 39.
17. M.S. El-Samaligy, N.N. Afifi, E.A. Mahmoud .Increasing bioavailability of silymarin using a buccal liposomal delivery system: Preparation and experimental design investigation. International Journal of Pharmaceutics 2006; 308:140–148.
18. Libero Italo Giannola , Viviana De Caro , Giulia Giandalia ,Maria Gabriella Siragusa , Claudio Tripodo , Ada Maria Florena , Giuseppina Campisi . Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design. European Journal of Pharmaceutics and Biopharmaceutics. 2007.
19. Ana Figueiras , Rui A. Carvalho , Laura Ribeiro , Juan J. Torres-Labandeira Francisco J.B. Veiga .Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified b-cyclodextrin.ssuropean Journal of Pharmaceutics and Biopharmaceutics. 2007.
20. Axel Schneeweis, Christel C. Muller-Goymann. Controlled release of solid-reversed-micellarsolution (SRMS) suppositories containing metoclopramide-HCl. International Journal of Pharmaceutics. 2000; 196:193–196.
21. Ulrich Klotz, Matthias Schwab .Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease. Advanced Drug Delivery. 2005; 57:267-279.
22. ST Lim, B Forbes, GP Martin, and MB Brown. In vivo and in vitro characterization of novel micro particulates based on hyaluronan and chitosan hydroglutamate.AAPS PharmSciTech2001; 2 (4) article
23. Sambhaji Pisal, Vijay Shelke, Kakasaheb Mahadik,Shivajirao Kadam. Effect of organogel components on in vitro nasal delivery of propranolol hydrochloride. AAPS PharmSciTech 2004; 5 (4) Article 63.
24. E. Gavini , A.B. Hegge , G. Rassu a, V. Sanna , C. Testa ,G. Pirisino , J. Karlsen , P. Giunchedi.Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies. International Journal of Pharmaceutics .2006; 307:9-15.
25. Sonal R. Patel , Hui Zhong , Ashutosh Sharma , Yogeshvar N. Kalia. In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.European Journal of Pharmaceutics and Biopharmaceutics.2007; 66: 296–301.
26. Hongxia Lin , Matthias Gebhardt , Shengjie Bian , Kyoung Ae Kwon ,Chang-Koo Shim, Suk-Jae Chung, Dae-Duk Kim. Enhancing effect of surfactants on fexofenadine·HCl transport across the human nasal epithelial cell monolayer. International Journal of Pharmaceutics.2007; 330:23–31.
27. Jean-Louis Bourges, Sandrine E. Gautier, Florence Delie, Riad A. Bejjani, Jean-Claude Jeanny, Robert Gurny, David Ben Ezra, and Francine F. Behar-Cohen. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticses. Investigative
Ophthalmology and Visual Science. 2003; 44:3562-3569.
28. De Campos A.M.;Diebold Y.;Carvalho E.L.S.;Sánchez A.,José Alonso M. Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability, in vivo fate, and cellular toxicity. Pharmaceutical Research, Springer. 2004; 21(5): 803-810(8).
29. Alvarez-Lorenzo, C., Hiratani, H., & Concheiro, A. (2006). Contact lenses for drug delivery: Achieving sustained release with novel systems. American Journal of Drug Delivery, 4, 131-151.
30. American Heart Association. (2005). Management of cardiac arrest recommended by the American Heart Association. Retrieved June 23, 2008, from http://circ.ahajournals.org/cgi/ content/full/112/24_suppl/IV-58
31. Bajwa, Z., & Warfield, C. (2008). Interventional approaches to the management of cancer pain. Retrieved on May 13, 2008, from www.uptodate.com
32. Bielinska, A., Janxzak, K., & Landers, J. (2008). Nasal immunization with a recombinant HIV gp120 and nanoemulsion adjuvant produces Thl polarized responses and neutralizing antibodies to primary HIV type isolates. AIDS Research and Human Retroviruses, 24, 271-281.
33. Bulletin Board. (2008). Nanomedicine, 3, 145-147. 34. Canadian Press. (2008). Canadian researchers develop automated anesthesia system dubbed McSleepy. Retrieved May 6, 2008, from www.googlenews.com 35. Chandhari, M., & Mackenzie, P. (2007). Implantable technology for pain management. Anaesthesia & Intensive Care Medicine, 9, 69-74. 36. Clinical Trials. (2008, February). BioDelivery sciences to present BEMA fentanyl data at the 24th Annual Meeting of the American Academy of Pain Medicine. Retrieved on May 15, 2008, from http://www.drugs.corn/clinical_trials/biodeliverysciences-present- bema-fentanyl-data-24t 37. Cox, C. (n.d.). Treatment options gel with innovative drug delivery systems. Drug Delivery Technology Retrieved on May 16, 2008, from http://www.drugdeliverytech.com/cgi-bin/articles. cgi?idArticle=55 38. Gotfried, M. H., Shaw, J. P., Benton, B. M., Krause, K. M., Goldberg, M. R., Kitt, M. M., et al. (2008). Intrapulmonary distribution of intravenous televancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of televancin and other antibiotics. Antimicrobial Agents and Chemotherapy, 52, 92-97. 39. Hafeli, U. (2004). Magnetically modulated therapeutic systems. International Journal of Pharmaceutics, 277, 19-24. 40. Hirlekar, R., Patel, P, & Dand, N. (2008). Drug loaded erythrocytes: As novel drug delivery system. Current Pharmaceutical Design, 14, 63 70. 41. in-Pharma Technologist.com. (January 10, 2005). Contact lenses deliver drugs to eye. Retrieved on May 30, 2008, from http:// www.in-pharmatechnologist.com/news/ng.asp?id=57187-contactlenses-deliver 42. Irani, F., Dankert, M., Brensinger, C., Bilker, W., Nair, S., Kohler, C., et al. (2004). Patient attitudes towards surgically implantable, long-term delivery of psychiatric medicine.
Neuropsychopharmacology, 29, 960-968. 43. Jeng, M. J., Lee, Y. S., & Soong, W. J. (2007). Effects of perfluorochemicals for intrapulmonary vancomycin administration and partial liquid ventilation in an animal model of meconium-injured lungs. Acta Paediatrica Taiwanica, 48, 309-316. 44. Leary, S., Liu, C., & Apuzzo, M. (2006). Toward the emergence of nanoneurosurgery: Part II-Nanomedicine: Diagnostics and imaging at the nanoscale level. Neurosurgery, 58, 805-823. 45. Maloney, J., Uhland, S., & Polito, B. (2005). Electrothermally activated microchips for implantable drug delivery and biosensing. Journal of Controlled Release, 109, 244 255. 46. Medscape Medical News. (2002). 'Pain relief ball' cuts opioid use after gynecologic surgery. Retrieved on March 16, 2008, from http://wwwmedscape.com/viewarticle/433317
47. Morrow, J., Bawa, R., & Wei, C. (2007). Recent advances in basic and clinical nanomedicine. Medical Clinics of North America, 91,805 843. 48. Nova Science Now. (n.d.). Cancer nanotech. Retrieved May 10, 2008, from
http://www.pbs.org/wgbh/nova/sciencenow/3209/ 03-canc-nf.html 49. Skryabina, E., & Dunn, T. (2006). Disposable infusion pumps. American Journal of Health System Pharmacists, 63, 1260 1268. 50. Tasciotti, E., Liu, X., & Bhavane, R. (2008). Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nature Nanotechnology, 3, 151 157. 51. Triangle Business Journal. (2008, May). BDSI's pain patch does well in human trial. Retrieved May 30, 2008 from http:// triangle.bizjournals.com/triangle/stories/2008/05/05/daily28. html 52. Wermeling, D. P, Miller, J. L., & Rudy, A. C. (n.d.). Systemic" Intranasal drug delivery: concepts and applications. Drug Delivery Technology. Retrieved March 16, 2008, from http://www. drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=22 53. Wynne, A. L., Woo, T. M., & Olyaei, A. J. (2007). Pharmacotherapeutics for nurse practitioner prescribers (2nd ed.). Philadelphia: EA. Davis. 54. Yih, T., & Al-Fandi, M. (2006). Engineered nano particles as precise drug delivery systems. Journal of Cellular Biochemistry, 97, 1184-1190. 55. Young, E. (2004). Drug-delivering contact lenses revealed. NewScientist.com news service. Retrieved June 1,2008, from http://newsscientist.com/article.ns?id=dn6597 56. Angelia Colwell Berkowitz, BSN RN CRNI, is a graduate student at The University of Texas Health Science Center at San Antonio, San Antonio, TX. 57. The next series shall comprise of the formulation challenges as well as quality considerations and regulatory challenges faced during the development of mucosal DDS. 58. www. Pharm-Education.com
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.