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Pharmaceutical Biotechnology PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Pharmaceutical Biotechnology" by Dr Athmar Dhahir Habeeb.

This medical PowerPoint presentation is about pharmaceutical biotechnology, the branch of biotechnology that is specifically focused on the development of drugs and other therapeutic products using biological processes. This field is interdisciplinary, drawing on knowledge from biology, chemistry, pharmacology, and other related disciplines.

Pharmaceutical biotechnology involves the use of living organisms or their products, such as enzymes or antibodies, to produce drugs. This can include the use of genetic engineering to modify the DNA of organisms, such as bacteria or yeast, to produce specific proteins that are used as drugs.

One important area of pharmaceutical biotechnology is the development of biologics, which are drugs made from biological sources, such as proteins, antibodies, and nucleic acids. Biologics are often used to treat complex diseases such as cancer and autoimmune disorders.

Pharmaceutical biotechnology also encompasses the development of biosimilars, which are drugs that are similar to existing biologics but are not exact copies. Biosimilars are designed to provide an affordable alternative to expensive biologics while maintaining the same efficacy and safety profile.

Overall, pharmaceutical biotechnology plays a critical role in the development of new drugs and therapies that can improve patient health and well-being.

Tags : Pharmaceutical Biotechnology, development of drugs, pharmaceuticals, pharmaceuticals PowerPoint presentations

Published on : Jun 23, 2023 | Views : 2521 | Downloads : 5

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Slide 1-

Pharmaceutical Biotechnology Advanced drug delivery Dr Athmar Dhahir Habeeb PhD in Industrial Pharmacy and pharmaceutical formulations
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Biotechnology is the use of microorganisms, plants, animals or parts of them for the production of useful compounds and Pharmaceutical biotechnology is concerned as the biotechnological manufacturing of pharmaceutical products. An insight into the nature of the traditional processes was achieved in about 1870 when Pasteur illustrated that chemical conversions in these processes were performed by living cells, and thus the traditional processes should be consider biochemical conversions. Pharmaceutical Biotechnology
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Decades following Pasteur's discovery, biotechnological knowledge increased when the catalytic role of enzymes for most biochemical conversions became apparent, based on that knowledge tools became available for the control and optimization of the traditional processes A further and very important breakthrough took place after the development of (Molecular Biology). The notion or concept, brought forward by the pioneers in the molecular biology in around 1950, that DNA encodes proteins and in this way controls all cellular processes was the impetus for a new period in biotechnology.
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The fast evolving DNA technologies, after the development of the recombinant DNA technology in 70th, allowed biotechnologists to control gene expression in the organisms used for biotechnological manufacturing. These developed technologies opened new ways for the introduction of foreign DNA into all kinds of organisms. Thus genetically modified organisms constructed in this way to open up completely new possibilities for biotechnology.
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Complex biological molecules, commonly known as proteins that usually aim at eliminating the underlying mechanisms for treating diseases. Essentially used to make (Complex Larger Molecules) with the help of living cells (like those found in the human body such as bacteria cells, yeast cells, animals or plant cells). Unlike the smaller molecules that are given to a patient through tablets, the large molecules are typically injected into the patient’s body. Biopharmaceuticals
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Antibodies- are proteins produced by white blood cells and are used by immune system to identify bacteria, viruses and other foreign substances and to fight them off. Monoclonal antibodies- are one of the most exciting developments in pharmaceutical biotechnology at these recent years. (produced as a result of perpetuating the expression of a single beta lymphocyte. Consequently, all of the antibody molecules secreted by a series of daughter cells derived from a single dividing parent beta lymphocyte are genetically identical). Pharmaceutical Biotechnology Products Antibodies, Proteins and Recombinant DNA products
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Proteins- made of amino acids or large, complex molecules that do most of the work in the cells and are required for the structure, function, and regulation of the body’s tissues and organs. Protein biotechnology- is emerging as one of the key technologies of the future for understanding the development of many diseases like cancer or amyloid formation for better therapeutic intervention.
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Recombinant DNA TechnologiesGenetic modification of organisms is done by Fusion of any DNA fragment to DNA molecules able to maintain themselves by autonomous replication. Such molecules called replicons
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Recombinant DNA Plasmid or Vector
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Recombinant DNA technology or DNA cloning technology: (Application of plasmids in biotechnology) Fusing foreign DNA fragment to the isolated plasmid in order to create a recombinant DNA molecule called replicons. Replicons used as carriers for foreign DNA fragments are termed vectors (include plasmids from bacteria or yeast, or DNA from bactriovirus, animal virus or Plant virus). Foreign DNA- isolated either from microbial, plant or animal cell Restriction enzyme used to cut DNA at a specific site. Ligase enzyme used to close circular recombinant DNA. Introduction of recombinant DNA into host cell leads to form (Transformant). Vector replicate in the host, thus all daughter cells will inherit precise copy (a clone) of the recombinant DNA molecule.
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Monoclonal Antibodies Typically made by fusing myeloma cells with the spleen from a mouse that has been immunized with the desired antigen.
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Laboratory animals (mammal, e.g. mice) are first exposed to the antigen that an antibody is to be generated against. Usually this is done by a series of injections of the antigen in question, over the course of several weeks. Once spleen cells are isolated from the spleen the B cells are fused with immortalised myeloma cells. The myeloma cells are selected beforehand to ensure they are not secreting antibody themselves and that they lack the (HGPRT) gene, making them sensitive to the incubation in HAT medium . Fused cells are incubated in HAT medium for roughly 10 to 14 days. Hence, unfused myeloma cells die, because they lack HGPRT. Removal of the unfused myeloma cells is necessary because they have the potential to outgrow other cells, especially weakly established hybridomas. Unfused B cells die as they have a short life span. In this way, only the B cell-myeloma hybrids survival. These cells produce antibodies (a property of B cells) and are immortal (a property of myeloma cells). The next stage is a rapid primary screening process, which identifies and selects only those hybridomas that produce antibodies of appropriate specificity. The B cell that produces the desired antibodies can be cloned to produce many identical daughter clones. Once a hybridoma colony is established, it will continually grow in culture medium and produce antibodies.
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Sterility Most proteins are administered parenterally and it should be sterile (But are sensitive to heat and other sterilization treatments) so cannot withstand [autoclaving, gas sterilization, or sterilization by ionizing radiation]. Protein pharmaceuticals assembled under aseptic conditions, following established and evolving rules in the pharmaceutical industry for aseptic manufacture. Formulation of Biotech ProductsBiopharmaceutical Considerations
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2.Viral Decontamination As recombinant DNA products are grown in microorganisms, these organisms should be tested for viral contaminants and appropriate measures should be taken if viral contamination occurs. Excipients with a certain risk factor, such as blood derived human serum albumin, should be carefully tested before use and their presence in the formulation process should be minimized. 3.Pyrogen removal Pyrogens are compounds that induce fever. Exogenous pyrogens (pyrogens introduced into the body, not generated by the body itself) can be derived from bacterial, viral or fungal sources. Bacterial pyrogens are mainly endotoxins shed from gram negative bacteria. They are lipopolysaccharides. Pyrogen removal of recombinant products derived from bacterial sources should be an integral part of preparation process: Excipients used in the protein formulation should be essentially endotoxins-free.
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Continuous with Pyrogen removal Pyrogen removal of recombinant products derived from bacterial sources should be an integral part of preparation process: Ion exchange chromatographic procedures (utilizing its negative charge) can effectively reduce endotoxins levels in solution. For solutions, water for injection (compendial standards) is (freshly) distilled or produced by reverse osmosis.
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Ion exchange chromatography
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In a protein formulation (active substance), a number of excipients selected to serve different purposes. The nature of the protein (e.g. lability-rapid change or destroyed-) and its therapeutic use (e.g. multiple injection systems) can make these formulations quite complex in term of excipients profile and technology (freeze-drying, aseptic preparation). Excipients Used in Parenteral Formulations of Biotech Product
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components found in parenteral formulations of biotech products Active ingredient Solubility enhancers Anti-adsorption and anti-aggregation agents Buffer components Preservatives and anti-oxidants Lyoprotectants/ cake formers Osmotic agents Carrier system Note: All of the above are not necessarily present in one particular protein formulation
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2. Solubility Enhancers Proteins, in particular those that are non-glycosylated, may have a tendency to aggregate and precipitate. Approaches that can be used to enhance solubility include: 1. Selection of the proper pH and ionic strength conditions 2. Addition of amino acids, such as lysine or arginine (used to solubilize tissue plasminogen activator, t-PA) 3. Addition of surfactants such as sodium dodecylsulfate, to solubilize non-glycosylate, IL-2 (interleukin-2) can also help to increase the solubility.
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Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat embolic or thrombotic stroke. tPA may be manufactured using recombinant biotechnology techniques. tPA created by this way may be referred to as recombinant tissue plasminogen activator (rtPA). Notes Interleukin 2 (IL-2) is an interleukin, a type of cytokine signalling molecule in the immune system. It is a protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity.
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The mechanism of action of these solubility enhancers Type of enhancer and protein involved and is not always fully understood. depends on
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Figure 1: Shows the effect of arginine concentration on the solubility of t-PA (alteplase) at pH 7.2 and 25oC. Arginine-phosphate (M) A : type I alteplase B : type II alteplase C : 50:50 mixture of type I and type II alteplase
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In the above examples aggregation is physical in nature, i.e. based on hydrophobic and/ or electrostatic interactions between molecules by formation of covalent bridges between molecules through disulfide bonds, and ester or amide linkages. In these cases proper conditions should be found to avoid these chemical reactions (the figure above clearly indicates the dramatic effect of this basic amino acid on the apparent solubility of t-PA).
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Anti-adsorption agents (added to reduce adsorption of the active protein to interfaces). Some proteins normally have hydrophobic sites in the core structure. They tend to expose hydrophobic sites when an interface is present. These interfaces can be water/air, water/container wall or interfaces formed between the aqueous phase and utensils used to administer the drug (e.g. catheter, needle). 3. Anti-adsorption and anti-aggregation agents
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These adsorbed, partially unfolded protein molecules form aggregates, leave the surface, return to the aqueous phase, form larger aggregates and precipitate. Example: The proposed mechanism for aggregation of insulin in aqueous media through contact with a hydrophobic surface (or water-air interface) is presented in Figure 2.
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Figure 2 Reversible self-association of insulin, its adsorption to the hydrophobic interface and irreversible aggregation in the adsorbed protein film crystal Hydrophobic surface Aqueous solution monomer Dimer Hexamer Tetramer
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Native insulin in solution is in an equilibrium state between monomeric, dimeric, tetrameric and hexameric form. The relative abundance of the different aggregation states depends on the pH, insulin concentration, ionic strength and specific excipients (Zn2+ and phenol). Suggestion: dimeric form of insulin adsorbs to hydrophobic interfaces and subsequently forms larger aggregates at the interface. This adsorption explains why anti-adhesion agents can also act as anti-aggregation agents.
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Ex: Albumin (strong tendency to adsorb to surfaces) and is therefore added in relatively high concentration (e.g. 1%) as an anti-adhesion agent to protein formulations. Mechanism: albumin competes with the therapeutic protein for binding sites and prevents adhesion of the therapeutically active agent by combination of its binding tendency and abundant presence.
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Insulin is one of the many proteins that can form fibrillar precipitates (long rod-shaped structures with diameters in the 0.1 µm range). Low concentrations of phospholipids and surfactants (as a fibrillation-inhibitory effect). The selection of the proper pH to prevent this unwanted phenomenon. This can be prevented by: Apart from albumin, surfactants can also prevent adhesion to interfaces and precipitation. Readily adsorb to hydrophobic interfaces with their own hydrophobic groups and render this interface hydrophilic by exposing their hydrophilic groups phase.
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4. Buffer components Buffer selection is an important part of the formulation process, because of the pH dependence of protein solubility , physical and chemical stability. Buffer systems regularly encountered in biotech formulations are: phosphate citrate acetate
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The isoelectric point (pI) pH of a solution at which the net primary charge of a protein becomes zero. At a solution pH that is above the pI the surface of the protein is predominantly negatively charged and like-charged molecules will exhibit repulsive forces. At a solution pH that is below the pI, the surface of the protein is predominantly positively charged and repulsion between proteins occurs. At the pI the negative and positive charges cancel, repulsive electrostatic forces are reduced and the attraction forces predominate. The attraction forces will cause aggregation and precipitation. The pI of most proteins is in the pH range of 4-6.
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Figure 1. A plot of the solubility of various forms of hGH as a function of pH. The closed symbols mean that precipitate was present in the dialysis tube after equilibration, whereas open symbols mean that no solid material was present, and thus the solubility is at least this amount. Circles = recombinant hGH Triangles = Met-hGH Squares = pituitary hGH A good example of importance of the isoelectric point (its negative logarithm [pH] is equal to pI) is the solubility profile of human growth hormone (hGH, pI around 5) as presented in Figure 1: pI: is the pH at a particular molecule carries no net electrical charges (overall charge). Thus molecule is affected by pH of its surrounding environment and can become more positively or negatively charged due to the gain or loss, respectively, of (H+). Such molecules have minimum solubility in water or salt solutions at the pH that corresponds to their pI and often ppt. out of solution. +ve charge -ve charge
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Even short, temporary pH changes can cause aggregation. Explain why? These conditions can occur, for example, during the freeze-drying process, when one of the buffer components is crystallizing and the other is not. In a phosphate buffer, Na2HPO4 crystallizes faster than NaH2PO4. drop in pH during the freezing step. While other buffer components do not crystallize, but form amorphous systems and then pH changes are minimized.
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5. Preservatives and Anti-oxidants Methionine, cysteine, tryptophane, tyrosine and histidine are amino acids that are readily oxidized. Proteins rich in these amino acids are susceptible to oxidative degradation. Replacement of oxygen by inert gases in the vials helps to reduce oxidative stress. Addition of anti-oxidant such as ascorbic acid or sodium formaldehyde sulfoxylate can be considered. The solution !!! Antioxidants
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Certain proteins are formulated in the container designed for multiple injection schemes. After administering the first dose, contamination with microorganism may occur and the preservatives are needed to minimize growth. Usually, these preservatives are present in concentrations that are bacteriostatic rather than bactericide in nature. Antimicrobial agents mentioned in the USP XXIV are the mercury-containing pheylmercuric nitrate, thimerosal, p-hydroxybenzoic acids, phenol, benzyl alcohol and chlorobutanol. Preservatives
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Shelf Life of Protein Based Pharmaceuticals Protein can be stored: (1) as an aqueous solution (2) in freeze-dried form (3) in dried form in a compacted state (tablet). The stability of protein solutions strongly depends on factors such as pH, ionic strength, temperature, and the presence of stabilizers. E.g.: Figure 2 shows the pH dependence of α1-antitrypsin and clearly demonstrates the critical importance of pH on the shelf-life of proteins.
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Freeze-Drying of Proteins Proteins in solution often do not meet the preferred stability requirements for industrially pharmaceutical products (>2 years), even when kept permanently under refrigerator conditions (cold chain). The abundant presence of water promotes chemical and physical degradation processes.
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Importance of Freeze Drying Freeze-drying may provide the desired stability by extending shelf life. During freeze-drying water is removed via sublimation and not by evaporation. it works by freezing the material, then reducing the pressure and adding heat to allow the frozen water in the material to sublimate. Three stages can be discerned in the freeze-drying process: (1) freezing step (2) primary drying step (3) secondary drying step.
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Table 1. Three stages in the freeze drying process of protein formulations. Freezing The temperature of the product is reduced from ambient temperature to a temperature below the eutectic temperature (Te), or below the glass transition temperature (Tg) of the system. A Tg is encountered if amorphous phases are present. Primary drying Crystallized and water not bound to protein/excipients is removed by sublimation. The temperature is below the Te or Tg; the temperature is for example -40oC and reduced pressures are used. Secondary drying Removal of water interacting with the protein and excipients. The temperature in the chamber is kept below Tg and rises gradually, e.g., from -40oC to 20oC.
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The freeze-drying of a protein solution without the proper excipients causes, as a rule, irreversible damage to the protein. Table 4.3 lists excipients typically encountered in successfully freeze-drying protein products:
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Table 4.3. typical excipients in a freeze-dried protein formulation Bulking agents: mannitol/ glycine Reason: elegance/ blowout prevention Blowout is the loss of material taken away by the water vapor that leaves the vial. It occurs when little solid material is present in the vial. Collapse temperature modifier: dextran, albumin/ gelatine Reason: prevent increase collapse temperature. Lyoprotectant: sugars, albumin Reason: protection of the physical structure of the protein. Mechanism of action of lyoprotectants is not fully understood. Factors that might play a role are:
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Mechanisms of action of lyoprotectants Lyoprotectants replace water as stabilizing agent (water replacement theory), Lyoprotectants increase the Tg of the cake/ frozen system Lyoprotectants will absorb moisture from the stoppers Lyoprotectants slow down the secondary drying process and minimize the chances for overdrying of the protein. Overdrying might occur when residual water levels after secondary drying become too low.
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The parenteral Route of Administration Parenteral administration is defined as administration via those routes where a needle is used, including intravenous (IV), intramuscular (IM), subcutaneous (SC) and intraperitoneal (IP) injections. The blood half-life of biotech products can vary over a wide range. For example, the circulation half-life of t-PA is a few minutes, while monoclonal antibodies (MAB) have half-lives of a few days Delivery of Proteins
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One reason to develop modified proteins through site directed mutagenesis To enhance circulation half-life. By expanding the mean residence time for short half-life proteins (switch from IV to IM or SC administration). 1- changes in disposition which Have a significant impact on the therapeutic performance of the drug.
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These changes are related to: The prolonged residence time at the IM or SC site of injection compared to IV administration and enhanced exposure to degradation reactions (peptidases). Differences in disposition.
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Regarding point 1 (Prolonged residence time at IM or SC site of injection and the enhanced exposure to degradation reactions.) A- For instance, diabetics can become “insulin resistant” through high tissue dipeptidyl peptidase {DPP-IV} activity . B- Other factors that can contribute to absorption variation are related to differences in exercise level of the muscle at the injection site. C- The state of the tissue, for instance the occurrence of pathological conditions, may be important as well.
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Regarding point 2 (Differences in disposition). Upon administration, the protein may be transported to the blood circulation or through the lymphatics through the capillary wall at the site of injection. Note: The fraction of the administered dose taking this lymphatic route is molecular weight dependent.
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Routes of uptake of SC or IM injected drugs Blood Capillary wall lymph Low Mwt drugs Site of injection High Mwt drugs
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Molecular weight of different proteins rIFN alpha-2a (Mw 19 kDa) Cytochrome C (Mw 12.3 kDa) Inulin (Mw 5.2 kDa) FUdR (Mw 256.2 Da) The following Figure shows: Cumulative recovery in the efferent lymph from the right popliteal lymph node following SC administration into the lower part of the right hind leg of sheep
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Correlation between the molecular weight and cumulative recovery
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Lymphatic transport takes time (hours) and uptake in the blood circulation is highly dependent on the injection site. On its way to the blood, the lymph passes through draining lymph nodes and contact is possible between lymph contents and cells of the immune system such as macrophages, B- and T-lymphocytes residing in the lymph nodes.
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The Oral Route of Administration Oral delivery of protein drugs would be preferable because: It is patient friendly No intervention by a healthcare professional is necessary to administer the drug. Not Preferable: Oral bioavailability is usually very low. The two main reasons for failure of uptake after oral administration Protein degradation in the gastrointestinal (GI) tract. Poor permeability of the wall of the GI tract in case of a passive transport process.
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(protein degradation in the GI tract) The human body has developed a very efficient system to break down proteins in our food to amino acids, or di- or tri-peptides. These building stones for body proteins are actively absorbed for use wherever necessary in the body. In the stomach pepsins (a family of aspartic proteases) are secreted. They are particularly active between pH 3 and 5 and lose activity at higher pH values. Pepsins are endopeptidases capable of cleaving peptide bonds distant from the ends of the peptide chain. They preferentially (cleave peptide bonds between two hydrophobic amino acids). Other endopeptidases are active in the GI tract at neutral pH values, e.g., trypsin, chymotrypsin, and elastase. They have different peptide bond cleavage characteristics that more or less complement each other. Exopeptidases, proteases degrading peptide chains from their ends, are present as well. Examples are carboxypeptidase A and B.
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In the GI lumen the proteins are cut into fragments that effectively further break down to amino acids, di- and tri-peptides by brush border (microvillus) and cytoplasmic proteases of the enterocytes (intestinal absorptive cells).
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(permeability) High molecular weight molecules do not readily penetrate the intact and mature epithelial barrier if diffusion is the sole driving force for mass transfer. Their diffusion coefficient decreases with increasing molecule size. Protein are no exception to this rule. Active transport of intact therapeutic recombinant proteins over the GI-epithelium has not been described yet.
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Conclusion The above analysis leads to the conclusion that the oral route of administration for therapeutic protein is unsuitable if high (or at least constant) bioavailability is required.
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However, for the category of oral vaccines the above-mentioned hurdles of degradation and permeation are not necessarily prohibitive. Ex: For oral immunization, only a (small) fraction of the antigen (protein) has to reach its target site to elicit an immune response. The target cells are B-lymphocyte cells that produce secretory IgA antibodies. and antigen presenting accessory cells located in Peyer’s patches (macroscopically identifiable follicular structures located in the wall of the GI tract).
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Peyer’s patches are overlaid with microfold (M) cells (separate the luminal contents from the lymphocytes). These M cells have little lysosomal degradation capacity and allow for antigen sampling by the underlying lymphocytes. Moreover, mucus producing goblet cell density is reduced over Peyer’s patches. This reduces mucus production and facilitates access to the M cell surface for luminal contents. Attempts to improve antigene delivery via the Peyer’s patches and to enhance the immune response are made by using microspheres, liposomes or modified live vectors, such as attenuated bacteria and viruses.
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Parenteral administration has disadvantages (needles, sterility, injection skill) compared to other possible routes. Delivery through nose, lungs, rectum, oral cavity, and skin have been selected as potential sites of application. Alternative Route of Administration
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Nasal Advantage: Easily accessible Fast uptake Proven track record with a number of “conventional” drugs Probably lower proteolytic activity than in the GI tract Avoidance of first pass effect Spatial containment of absorption enhancers [osmolarity & pH] is possible (when drugs exhibits poor membrane permeability, large molecular size, lack of lipophilicity and enzymatic degradation by amino peptidases). The potential pros and cons for different relevant routes
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Nasal Disadvantage: Reproducibility (in particular under intranasal pathologies may affect or capacity for nasal absorption) Safety (e.g., cilliary movement that propelled proteins into the throat where it is swallowed and destroyed by the products of the stomach). Low bioavailability for proteins (Because they are large molecular weight polar drugs thus they have low membrane permeability).
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Pulmonary (intratracheal inhalation or instillation) Advantage: Relative easy to access (aerosol or syringe). Fast uptake. Proven track record with “conventional” drugs. Substantial fractions of insulin are absorbed. Lower proteolytic activity than in the GI tract. Avoidance of hepatic first pass effect. Spatial containment of absorption enhancer.
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Pulmonary Disadvantage: Reproducibility (in particular under pathological conditions, smoker/non-smoker). Safety (e.g., inhaled human insulin [powder or liquid] has been shown to be more immunogenic than comparator insulins given by S.C. routes; however, adverse effects of antibody formation demonstrated) Presence of macrophages in the lung with affinity for particulates.
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Rectal Advantage: Easily accessible Partial avoidance of hepatic first pass Probably lower proteolytic activity than in the upper parts of GI tract Spatial containment of absorption enhancers is possible Proven track record with a number of “conventional” drugs. Disadvantage: Low bioavailability for proteins
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Buccal Advantage: Easily accessible Avoidance of hepatic first pass Probably lower proteolytic activity than in the lower parts of the GI tract Spatial containment of absorption enhancer is possible Option to remove formulation if necessary Disadvantage: Low bioavailability of proteins No proven track record yet.
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Transdermal Advantage: Easily accessible Avoidance of hepatic first pass Removal of formulation if necessary is possible Spatial containment of absorption enhancers Proven track record with “conventional” drugs Sustained/controlled release possible Disadvantage: Low bioavailability of proteins
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The nasal, buccal, rectal, and transdermal routes all have been shown to be of little clinical relevance if systemic action is required, and if simple protein formulations without an absorption enhancing technology are used. In general, bioavailability is too low and varies too much! The pulmonary route may be the exception to this rule (because in pulmonary the absorption was strongly protein dependent, with no clear relationship with it’s molecular weight). Conclusion
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In human the drug should be inhaled instead of intratracheally administered. The delivery of insulin to Type I (juvenile onset) and Type II (adult onset) diabetics has been extensively studied and clinical phase III trials evaluating efficacy and safety have been performed or are ongoing. The first pulmonary insulin formulation was approved by FDA in January 2006 (Exubera®). It was taken off the market 2008 because of poor market presentation
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Many pharmaceutical companies doing research in the field to develop an inhalational preparation announced the termination of product development following the poor acceptance and risk of lung cancer of the first US FDA approved inhaled insulin product, Exubera®. This formulation produced cough, dyspnoea (difficulty in breathing), increased sputum, and epistaxis (nosebleed), and was contraindicated in patients with chronic obstructive pulmonary disease (COPD) and asthma.
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Technosphere insulin: a new inhaled insulin MannKind Corporation has developed a powdered formulation of insulin with a higher percentage of absorption from the lungs. This product, Afrezza® (Technosphere® insulin), appears to have overcome some of the barriers that contributed to the withdrawal of Exubera® and is currently under review by the FDA.
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Technosphere insulin is a new inhaled insulin preparation which mimics normal prandial insulin release. It decreases post-prandial blood glucose (PPG) levels and has good glycaemic control with significantly lesser hypoglycaemia. Current data show that this formulation has no impact on pulmonary function. Long-term safety studies with regard to pulmonary function and risk for development of lung carcinoma need to be monitored. The FDA is currently reviewing Technosphere insulin for use in both type 1 and type 2 diabetes.
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Technosphere® insulin
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Approaches to enhance bioavailability of proteins
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Examples of Absorption Enhancing EffectsEffect of glycocholate (absorption enhancer) on nasal bioavailability of some proteins and peptides.
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Major issues now being addressed are reproducibility, effect of pathological conditions (e.g., rhinitis) on absorption and safety aspects of chronic use. Absorption enhancing effects were shown to be species dependent. Pronounced differences in effect were observed between rats, rabbits, and humans.