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Innovative Strategies and Models for R&D Success.

6/21/2017

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Over the last quarter of the twentieth century, medical research made substantial advances in defining our understanding of diseases, their etiologies, and the biochemical pathways through which they were mediated. Our understanding was further augmented by human genome research.
Picture
As the pathways of disease were clearly identified, pharmaceutical research largely focused on a “lab to market” approach, which involved identifying/synthesizing molecules that could mediate a disease pathway, characterizing their various attributes, and then commercializing them. In several cases, new molecules had characteristics that were marginally different from others already on the market, and therefore, did not address any unmet clinical need.

Commercial success was often determined by the intensity of the sales and marketing effort behind the product, which resulted in an “arms race” (a battle for maximizing share of voice by investing in larger and larger sales teams) and the emergence of “blockbusters.”  


The last 10 years have seen a seismic shift in the dynamics of pharmaceutical sales and marketing. The return on investment in sales force expansion is shrinking, causing almost all major pharmaceutical companies to reduce their head counts. Further, it is increasingly evident that the market and regulators are interested in new therapies that address an unmet need rather than yet another product in an existing class of molecules with little or no clinical or economic benefit.  

Over the last few years, most of the innovations in pharmaceutical development have been only incremental — for most indications, there are significant therapy options available and it is unlikely that a radically better “wonder drug” will become available soon. Consequently, a disproportionate amount of ongoing research and development (R&D) effort has gone into products already in the market to expand the spectrum of indications where they can be used. A look at the number of drugs approved by the US FDA over the years indicate 35 new drugs approved in 2005 as against only 20 last year. The decline in approvals is a clear indication of how difficult it will be for pharmaceutical companies to continue to show revenue growth in future.  

As they grapple with shrinking pipelines, stricter safety requirements of the regulator, and spiraling costs to bring a product to market, pharmaceutical companies need to ensure that their products genuinely fulfill an unmet market need. Therefore, it is imperative that the R&D effort follow a “market to lab” approach—one that reverses the conventional approach used over the last few decades. 

Aligning the organization to the Goals of Clinical Development-
Clinical R&D is a complicated process involving several steps and multiple stakeholders, both internal and external, in a pharmaceutical organization. Over the last 50 years, the journey of a product from laboratory to the market has not only become more arduous and time-consuming, but also more risky. Furthermore, since more and more clinical development plans (CDPs) include global, multi-centric clinical trials, their formulation and execution are broken into several sub-elements, each of which have become the responsibility of different functional silos in a pharmaceutical company. Consequently, clinical R&D at present involves stakeholders from the strategic, marketing, sales, medical, R&D, clinical operations, regulatory affairs, documentation, and health economics teams.  

Given that the collective objective of all the teams involved in the CDP is to achieve a desirable Target Product Profile (TPP) and therefore a superior product label, pharmaceutical companies must ensure that all stakeholders are aligned and share a common line of sight to the end objective. This is not always easy, but is a critical challenge that must be overcome. Failure to do so runs the risk of a CDP not being in step with current and future market needs, and oblivious to the competitive scenario in the future.  

The essence of “claims-based R&D” lies in taking a backward “market to lab” approach so as to ensure that the CDP is designed to address specific unmet market needs. It also involves the systematic benchmarking of a product’s CDP to current and future competition while continuously evaluating scientific and market threats and opportunities. It involves the integration of multiple inputs to develop the CDP and then prospectively simulate the likely TPP of the product and a SWOT analysis vis-à-vis its inline and pipeline competitors. 

The Process of Developing a CDP-
The process of claims-based R&D is iterative since it attempts to temper the desire to develop an “ideal” product with scientific and operational feasibility. With the ever-growing volume of information and data available in the secondary domain, it is now possible to pursue claims-based R&D to a far greater level of granularity than before. It also enables TPP simulation on a near real-time basis as pivotal information becomes available. 

Customer Insights-
In an earlier era of pharmaceutical development, unmet market needs were determined almost exclusively from the opinions of physicians and medical key opinion leaders (KOLs). In the modern era, however, there has been a significant shift in the level of influence exerted by different stakeholders (customers) on the patterns of pharmaceutical consumption. These stakeholders (customers) include the patient, the payor, and the regulator. 

While pursuing claims-based R&D, it is critical to ensure that the insights and opinions of all the key stakeholders (customers) are accurately captured so that the product(s) developed can genuinely claim to deliver a clinical and/or economic benefit. 

These insights are most often captured through primary research and intelligence initiatives, which include engagement with physician groups, patient and caregiver groups, insurance agencies, etc. However, such initiatives can be effectively complemented by research of secondary sources of information such as online patient discussions boards and transcripts of regulatory proceedings. 

Scientific Insights-
The volume of scientific research has been growing at an astounding rate. A search on www.pubmed.com (the online index of the National Library of Medicine) reveals that approximately 725,000 articles were published over the last year alone. Journal articles and congress presentations constitute a wealth of information about cutting-edge scientific developments.  

A thorough analysis of such publications and academic congresses is critical at the time of developing a CDP and simulating the TPP because:
  • It serves as an advanced warning system about novel scientific developments that could threaten to make obsolete a particular product.
  • It could reveal alternate approaches to addressing the unmet clinical need at an early stage, and therefore throw up opportunities for partnerships or ideas for development
  • It presents the successes and failures of competitive development programs, thereby sparing a lot of unnecessary effort and investment
  • It is a good source to unveil new information about the epidemiology of a disease and therefore the size of the addressable market opportunity. 

Competitor Insights-
Ultimately, pharmaceutical R&D needs to be viewed in the context of competition because of the underlying commercial objectives associated with the process. Consequently, an understanding of the development, licensing, and marketing strategies of the competition constitutes a critical input into the development of the CDP.  

It is important to note that competition needs to be viewed not merely in today’s context but also in context of what lies ahead. Therefore, it is recommended that any CDP and its derived TPP be benchmarked to the claims and positioning strategies of competitive products already in the market as well as the likely claims and strategies of pipeline products.  

Fortunately, substantial amount of information about clinical trials—completed and ongoing—is available in the public domain through sources such as product labels and clinical trial registries. The main source for clinical trial information is www.clinicaltrials.gov (the official site of the US FDA), which contains several essential details about all registered clinical trials. 

Although the information is accessible through sources such as the ones cited above, it is essential to note that deriving insights, simulating competitive claims, etc., is an exercise that requires substantial human expertise. 

The Ideal Target Product Profile-
As a first step of an iterative process to design a CDP, it is recommended to build an “ideal TPP.” To do this, one would need to integrate the various insights and inferences described above and evolve a TPP that would address all the unmet needs of the market while also yielding superior marketing claims across all product attributes.  

Therefore, an “ideal TPP” would represent best-in-class performance for efficacy, safety (ideally, would result in no adverse effects), tolerability, convenience, drug and food interactions, and perhaps, even cost. In addition, the “ideal TPP” would cover a wider patient population than all competitors. 

​The Real Target Product Profile (TPP)-
Much as we may aspire for an “ideal TPP,” it is necessary to recognize that in the real world, we cannot get every product attribute we desire. Therefore, we must modify the “ideal TPP” by prioritizing the attributes and claims that the CDP must focus on and compromising on others to arrive at the “real TPP.” This can be done by classifying the product attributes in the “ideal TPP” as either essential or desirable.  

The essential features of the TPP would represent a set of product attributes that represent either superiority over competing products or, at the very least, non-inferiority to competing products. Without these features, the product would enjoy no unique selling point when launched.  


The desirable features of the TPP would represent additional product attributes that could enhance the product’s marketability. These additional attributes could include some side indications, tolerability improvement, application for specific subpopulations, or even improved product stability. They all represent features that are not absolutely mandatory for commercial success but would certainly amplify the claim of superiority.​​
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Intranasal administration route for protein & peptide mucosal delivery.

6/6/2017

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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 administration route for protein & peptide mucosal delivery.Picture

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- 

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

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

3. 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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Nanotechnology in Mucosal Drug Delivery Systems

5/25/2017

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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).
Nanotechnology in mucosal drug delivery systems
"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 delivery, trans-git etc.
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Carriers used in Drug Targeting-

5/9/2017

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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. ​
carriers used in drug targeting
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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Formulation considerations in mucosal drug delivery- IV

4/14/2017

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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. ​
Formulations considerations of mucosal drug delivery
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 quarternary 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.
​


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Formulation Considerations In Mucosal Drug Delivery Systems - III

4/13/2017

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Methods used to study mucoadhesion: 

Several test methods have been reported for studying mucoadhesives. These tests are necessary not only to screen a large number of candidate mucoadhesives, but also to study their mechanisms. These tests are also important during the design and development of a bioadhesive modified release system as they ensure compatibility, physical and mechanical stability, surface analysis and bioadhesive bond strength. The test methods can broadly be classified into two major categories: ​
Mucosal drug delivery systems formulation considerations_ III
1. In vitro/ ex vivo methods; including: 

            - Measurement of tensile strength
            - Measurement of shear strength
            - Adhesion weight method
            - Fluorescent probe method
            - Flow channel method
            - Spectroscopic method
            - Falling liquid film method
            - Colloidal gold staining method
            - Viscometric method
            - Thumb test.
            - Adhesion number evaluation
            - Electrical conductance

 2. In vivo methods:

In vivo techniques for measuring bioadhesive strength are relatively few. Some of the reported methods are based on the measurement of the residence time of bioadhesives at the application site. The gastrointestinal transit time of many bioadhesives have been examined using radioisotopes. 

Bio/ Muco adhesive polymers: 

Polymers that adhere to the mucin- epithelial surface can be conveniently divide into three broad categories: 

1. Polymers that become sticky when placed in water and owe their bioadhesion to stickiness. 
2. Polymers that adhere through non-specific, noncovalent interactions, which are primarily electrostatic in nature. 
3.  Polymers that bind to specific receptor sites on the cell surface. 

All three-polymer types can be used for drug delivery. 

Characteristics of an ideal mucoadhesive polymer: 

The ideal polymer for a mucoadhesive drug delivery system should have the following characteristics: 

1. The polymer and its degradation products should be nontoxic and nonabsorbable from the gi tract. 
2. The polymers should be nonirritant to the mucous membrane. 
3. It should preferably form a strong noncovalent bond with the mucin- epithelial cell surface. 
4. It should adhere quickly to moist tissue and should possess some site specificity.
5. It should allow easy incorporation of the drug and offer no hindrance to its release.
6. The polymer must not decompose on storage or during the shelf life of the dosage form. 
7. The cost of the polymer should not be high, so that the prepared dosage form remains competitive. 

Several polymers viz. carbomers, celluloses e.g. sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose etc., guar gum, sodium alginate, polycarbophils etc. are being studied as potential mucoadhesive agents.
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Formulation considerations in mucosal drug delivery-II

4/12/2017

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Mucosal drug delivery systems formulation considerations_2
The rational approach for developing innovative polypeptide delivery system must therefore initially address two basic questions: 

  1. What is the rate & time course of systemic drug input (i.e. the input function i(t) that will maximize the therapeutic effect of the compound, minimize side effects and prevent if possible the development of tolerance (tachyphylaxis)?   
  2. What routes of administration (and associated pharmaceutical technologies) will provide the best means for achieving this input function in a safe, efficacious, reliable, “patient friendly” and cost-effective manner ? 

The following equation provides a simple theoretical framework for assessing the rate limiting steps responsible for the bioavailability (F) of polypeptides given by the transmucosal route: 

F  =[            TLM         ]           [               TM   ____]

            TLM + DL + EL          TMB  +  DM

Where in, 

L =       human, M   =   mucosa, B  =  bloodstream, EL  =Elimination from absorption site (pre absorption clearance) 

This mechanistic information is valuable for selecting appropriate routes of administration as well as for developing rational strategies to enhance the bioavailability.
​


Factors governing mucoadhesion:

The bioadhesive power of a polymer or a series of polymers is affected by the nature of the polymer and also by the nature of the surrounding media:

1. Polymer related factors: 

            - Molecular weight
            - Concentration of the active polymer
            - Flexibility of polymer chains
            - Spatial conformation
            - Polymer swelling index.

2. Environmental related factors:

            - pH
            - Applied strength of adhesives
            - Initial contact time
            - Selection of model substrate surface
            - Concentration of water or water content in substrate

3.Physiologic variables:

            - Mucin turn over
            - Disease state
            - Histology of organ (epithelial tissue)

In the next post we shall discuss on techniques used to study muco-adhesion.
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