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. 

Future developments-  

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/dispersion chambers and the drug storage systems, the main objective being ease of use. 

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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-  

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 mm. 

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. 

About the author:

Shruti Bhat PhD MBA Certified Lean Six Sigma Black Belt is Pharmaceutical R&D and Continuous Improvement Director, Innoworks Canada
Shruti leads path-breaking product development programs such as Complex Generics, Nanotechnology and Targeted delivery systems for pharmaceuticals and natural products. Her mantra is to "Shorten development timelines, build quality-by-design, lean processes and bring products fast- to- market". Shruti integrates her proficiency in Design Thinking, Lean, Kaizen and other Continuous Improvement methodologies to improve R&D processes, productivity and profitability.

Shruti is Product Development & Continuous Improvement Advisor to several start ups, mid-size and growing firms in Canada, USA, India, Africa and other Emerging markets. Shruti has authored six books and is an invited speaker at several conferences and workshops.  

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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 cm2) 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, patient-friendly 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.,). (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.). 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. 

Factors affecting nasal absorption- 

I.  Drug effect-  molecular size, lipophilic balance and ezymatic degradation in nasal cavity.  

II. Nasal effect-  membrane permeability (interspecies differences), environmental pH, mucociliary clearance, colds, rhinitis etc.

III.Delivery effect-  formulation (concentration, pH, Osmolality), delivery systems (sprays, drops, gels), deposition, formulation effects in mucociliary clearances, toxic effects on ciliary functions and epithelial membranes.

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. 

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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 x-rays, another that carries drugs to be released on demand, and one that sends a signal when cancerous cells are dead (Nova Science Now, n.d.). 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, other new methods of drug delivery continue to come to market, such as intranasal medications, pain balls, pulmonary deliver, trans-git etc. 

About the author:

Shruti Bhat PhD MBA Certified Lean Six Sigma Black Belt is Pharmaceutical R&D and Continuous Improvement Director, Innoworks Canada
Shruti leads path-breaking product development programs such as Complex Generics, Nanotechnology and Targeted delivery systems for pharmaceuticals and natural products. Her mantra is to "Shorten development timelines, build quality-by-design, lean processes and bring products fast- to- market". Shruti integrates her proficiency in Design Thinking, Lean, Kaizen and other Continuous Improvement methodologies to improve R&D processes, productivity and profitability.

Shruti is Product Development & Continuous Improvement Advisor to several start ups, mid-size and growing firms in Canada, USA, India, Africa and other Emerging markets. Shruti has authored six books and is an invited speaker at several conferences and workshops.
 
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Niosomes :

Niosomes non-ionic surfactant vesicles are similar to liposomes and can be prepared with cholesterol, a surfactant such as polysorbates (tweens) or sorbitanesters of fatty acids (spans) and water.  In general, niosomes are capable of releasing the entrapped drug slowly Methotrexate has been reincorporated into niosomes and the nature of the surfactant used seemed to affect the amount of methotrexate entrapped into the niosomes.  Furthermore, the pharmacokinetics of the methotrexate loaded niosomes in sarcoma S-180 bearing mice were comparable to those of the free drug.  The methotrexate plasma levels were higher and the rate of elimination from plasma was slower when the methotrexate-loaded niosomes were administered to tumor-bearing mice as compared with the free drug.

In conclusion, several cytotoxic agents, which had never been formulated before due to their low aqueous solubility, have been successfully incorporated into liposomes,  thereby decreasing the toxicity of the former formulation of the drug itself.  However, more research has to be performed to develop liposomes with higher chemical and physical stability to present degradation during extended storage.

Micro encapsulation System:

Micro encapsulation involves the application of a thin film of material and micronized solid or liquid to produce discrete units ranging in size from less than 1 m to several millimeters.  The products of micro encapsulation can be classified into nano particles (200-500nm), micro dispersions (0.5-m), micro spheres (1-100 m) and microcapsules (> 100 m).  Numerous methods have been used to prepare microencapsulated systems. These include pan coating, fluidized bed, spray drying, solvent evaporation, inter facial polymerization and coacervation techniques.

Microencapsulated systems often possess controlled release characteristics and less toxicity as compared to free drug.  These systems have been studied to target cytotoxic drugs viz. actinomycin D, 5-Fluorouracil, Doxorubicin, Vinblastin, etc.  However, they are unsuitable for formulation of thermolabile drugs. 

Cellular Carriers:

Erythrocytes, leukocytes, platelets, islets, hepatocytes, and fibroblasts, all have been suggested as potential carriers for drugs and biological substances.  They can be used to provide slow-release of entrapped drugs in the circulatory system, to deliver drugs to a specific site in the body, as cellular transplants to provide missing enzymes and hormones (in enzymes-hormone replacement therapy), or as endogenous cells to synthesize and secrete molecules that affect the metabolism and function of other cells.  Because these carriers are actual cells, they produce little or no antigenic response, and when old or damaged, they, like normal cells, are removed from the circulation by macrophages.  Another important feature of these carriers is that, once loaded with drug, they can be stored at 4o C for several hours to several days, depending on the storage medium and the entrapment method used.

Since erythrocytes, platelets, and leukocytes have received the greatest attention, the discussion that follows will be limited to these carriers.  Fibroblasts and hepatocytes have been specially used as viable sources to deliver missing enzymes in the management of enzyme deficiency diseases, whereas islets are useful as a cellular transplant to produce insulin.

Erythrocytes:

Erythrocytes have been suggested as potential carriers for a number of biologically active substances including drugs, nucleic acids and enzymes.  They can be used as storage depots for sustained-drug release or potentially be modified to permit targeting to specific cell types in the blood (e.g. direct targeting to cells in leukemia). 

Platelets:

Platelets have been used as a carrier for several biological substances and drugs useful in the management of various hematological diseases.  Platelets can accumulate drugs by selective active transport.  Certain drugs viz. angiotensin, hydrocortisone, imipramines, vinca alkaloids, (vinblastine and vincristine) and many other drugs are known to bind platelets.

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QUALITY CONTROL OF PEPTIDE/ PROTEIN  BASED PRODUCTS-  

To ensure efficacy and safety of a drug product, the active compound and its degraded product(s) must be quantified to determine the expiry period of the formulation. Due to the multiplicity of protein degradation pathways, no single test method can be guaranteed to be stability indicating. Only the continued information from various methods can lead to the assurance that the physicochemical integrity and biological activities of a protein are retained throughout manufacturing and shelf life. 

Peptide degradation have been reported as result of the following reasons-  

- Thermal denaturation (heat as well as cold)

- pH denaturation

- Salt denaturation

- Pressure and shear denaturation

- Surface denaturation and

- Freeze drying denaturation 

In addition to monitoring the integrity of the protein primary structure, protein conformation stability at secondary, tertiary and quaternary levels must also be verified to assure maintaining biological function.  

REGULATORY CONSIDERATIONS-  

Internationally, biotechnology products are regulated under the statutory authority of four federal agencies: the Food and Drug Administration, The Environmental Protection Agency, the Occupational Safety and Health Administration and the United Nations department of Agriculture. 

Unlike conventional drugs, peptides and protein drugs have primary, secondary and tertiary structures, all of which must be taken into account in order to gain complete control of the identity, strength, quality and potency of the material. As a result of this, establishing specific standards for the identity, strength, quality, potency and stability of peptide and protein drugs is a complex procedure; the use of the recombinant DNA (rDNA) techniques or hybridoma manufacturing process to produce peptides and proteins introduces additional complexities. 

CONCLUSION-  

Mucosal adhesive dosage forms are now at the starting line. The advantages are tremendous, which make further study in this field extremely important. The formulation of these drug delivery systems depends on the development of suitable polymers bearing excellent mucoadhesive properties, characteristics, size and molecular weight of peptides, their stability individually and in presence of mucoadhesive polymers and the overall biocompatibility of the dosage form. Obviously as the pharmaceutical industry moves into the area of peptide-based therapies, there will be greater stimulus for development of mucosal and like novel technologies of drug delivery.

About the author:

Shruti Bhat PhD MBA Certified Lean Six Sigma Black Belt is Pharmaceutical R&D and Continuous Improvement Director, Innoworks Canada
Shruti leads path-breaking product development programs such as Complex Generics, Nanotechnology and Targeted delivery systems for pharmaceuticals and natural products. Her mantra is to "Shorten development timelines, build quality-by-design, lean processes and bring products fast- to- market". Shruti integrates her proficiency in Design Thinking, Lean, Kaizen and other Continuous Improvement methodologies to improve R&D processes, productivity and profitability.

Shruti is Product Development & Continuous Improvement Advisor to several start ups, mid-size and growing firms in Canada, USA, India, Africa and other Emerging markets. Shruti has authored six books and is an invited speaker at several conferences and workshops.  

Social Media Connect:
Twitter https://twitter.com/ShrutiUBhat 
Facebook: https://www.facebook.com/DrShrutiUBhat
Website:  Http://www.ShrutiBhat.com   

#ShrutiBhat  #ContinuousImprovement  #LeanSixSigma  #LeanInnovation #TQM #Kaizen #PharmaceuticalR&D  #Innoworks

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