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`Biopharmaceutical Drug Delivery
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`™
`© 2024 MJH Life Sciences
`and BioPharm International.
`
`Biopharmaceutical Drug Delivery
`
`Published on: August 1, 2004
`BioPharm International
`BioPharm International, BioPharm International-08-15-2004, Volume 2004 Supplement, Issue 2
`
`Entire biopharmaceutical development projects can succeed or fail based on the feasibility of an acceptable dosage form. Therapeutic proteins
`range in size from a few hundred to over 100,000 Daltons. The biological manufacturing process leads to complex, unstable, and potentially
`variable products that frequently require novel dosage forms and new patterns of process validation.
`
`Entire biopharmaceutical development projects can succeed or fail based on the feasibility of an acceptable dosage form. Therapeutic proteins
`range in size from a few hundred to over 100,000 Daltons. The biological manufacturing process leads to complex, unstable, and potentially
`variable products that frequently require novel dosage forms and new patterns of process validation.
`
`By far the most common delivery method used in the biopharmaceutical industry is parenteral dosing; that is, liquid formulations for
`subcutaneous or intramuscular injection or intravenous drip. "An assured bioavailability will make this route the (cid:166)rst development objective,"
`explained D. Ganderton from the Chelsea Department of Pharmacy at King's College in London in Polypeptide and Protein Drugs: Production,
`Characterization, and Formulation. "Until a consistent bioavailability, which may be acceptable even if low, has been achieved, formulations
`derived for the oral route should not be included." Bioavailability measures how much of the drug molecule arrives at its site of action compared
`with how much is in the formulation delivered to the body.
`
`"In exploiting routes other than parenteral administration," Ganderton cautioned, "one encounters barriers for which there is little or no intrinsic
`permeation of the peptide. Breaching these barriers raises important questions of toxicity and, until massive research is carried out on the mode
`of action of penetration enhancers and the reversibility of their effects, a major regulatory hurdle will be raised against their use. In the meantime,
`much can be done to re(cid:166)ne parenteral dosage forms, both in terms of the time course of their action and the ease with which they are used."
`
`Ganderton wrote those words over a decade ago, but they still apply to most development projects today.
`
`Parental Drugs
`Scientists are re(cid:166)ning injectable delivery forms for better patient comfort, convenience, and compliance with dosage regimens. Three main
`technologies are under development: high-concentration formulations, needle-free injection devices, and controlled — sustained or targeted —
`delivery.
`
`High-concentration formulations. Comfort and e(cid:168)ciency of delivery limits the volume of subcutaneous injections to less than one milliliter per
`injection. The less volume a patient must receive in a single injection, the better. Many biopharmaceutical companies are exploring high-
`concentration formulations (>100 mg/mL) for protein drugs that require large doses, such as some monoclonal antibodies.
`
`The improper selection of (cid:166)lling equipment for high-concentration proteins will result in sheared, precipitated, aggregated, or adulterated
`solutions during the actual (cid:166)lling step. Traditional vial-(cid:166)lling methods (see Chapter 4) must be replaced by gentler technologies. For high-
`concentration formulations, lyophilization may be used to concentrate rather than preserve the formulation. The freeze-drying process removes
`water, and the formulation may be reconstituted by adding back into it a smaller quantity of water-for-injection.
`
`Questions yet to be answered about high-concentration formulations include the details of loading concentrations and (cid:166)ll volumes. The
`company's marketing department has a say here: Do end users want to see a vial with hardly anything in it? More technical questions arise over
`the higher concentrations of excipients in the product. Will stabilizing-excipients impede tonicity at high concentrations?
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`Needle-free injection. Another method for patients to self-administer their medications might be to completely dispense with the hypodermic
`needle. Medical device companies are developing methods of relatively painless needle-free injection, usually by high-pressure air or liquid that
`forces tiny droplets of a formulation through the skin. These technically are transdermal delivery devices.
`
`Another emerging technology is iontophoretic (electrically assisted) delivery. The skin is not naturally permeable to peptides and proteins; its
`main job (besides acting as the body's largest sensory organ) is precisely this kind of protection: keeping what's outside from getting inside.
`However, it can be induced to take a certain amount of very speci(cid:166)c material — a formulation on the skin, held in place by an adhesive that keeps
`other substances away from the delivery site — by an electric (cid:166)eld that temporarily changes the chemical and physical properties of the skin
`cells. As soon as that electrical (cid:166)eld is switched off, the skin returns to its normal state.
`
`Controlled delivery. Both the drug's duration (for sustained delivery) and its site (targeted delivery) of action and bioavailability can be controlled.
`Targeted delivery has been practiced for some time using monoclonal antibodies and surgical implantation, among other methods (see the
`"Blood-Brain Barrier" box on Page 22). Sustained delivery is gaining much interest in the biopharmaceutical arena.
`
`According to Nandini Katre of SkyePharma, "The major challenges in formulating therapeutic proteins and peptides for sustained delivery are as
`follows: maintaining the structural integrity of the therapeutic molecule to preserve its bioactivity and stability; obtaining high loading in the
`delivery vehicle to ensure su(cid:168)cient bioavailability for the duration of therapy; providing sustained therapeutic levels for the desired duration
`without a 'burst' effect, controlling the duration of drug release to accommodate a range of dosing regimens that match therapeutic needs; and
`providing in vivo biological effects that can be sustained over the required period of time."
`
`For sustained delivery, a depot (reservoir) of drug is created in the body (at the injection site, for example), from which the drug is released over a
`speci(cid:166)ed time. Biodegradable polymers open the possibility of implants that deliver a drug over days or months. Like any other method,
`sustained delivery presents certain challenges. In time, a protein may interact with its surrounding matrix, or the implant could be attacked by the
`immune system. If proteins stick (adsorb) to the delivery matrix, they may not be released at all. Even before implantation, creation of a delivery
`matrix often involves steps that can harm proteins. Four methods of creating a delivery matrix for sustained delivery can be used with
`biopharmaceuticals: emulsi(cid:166)cation, coacervation, extrusion, and polymerization.
`
`Emulsi(cid:166)cation. When the drug is water-soluble but the delivery matrix is not, they are dissolved into two different media and then mixed to create
`a water-in-oil emulsion. Usually, for better protein distribution, that emulsion is dispersed and mixed with a second aqueous solution to create a
`water-in-oil-in-water emulsion. The interfaces created by the droplets can denature proteins, especially when a series of emulsions are used to
`create the delivery matrix. Additionally, energy is required to combine the two (mechanical or ultrasonic mixing), which also can denature
`proteins.
`
`Coacervation. In coacervation, formulators add a competing molecule that is more soluble to a solution of the protein in liquid. The resulting
`chemical reactions create microspheres of the drug. This method is gentler than emulsi(cid:166)cation, but some loss of bioactivity can happen through
`pH changes and chemical reactions.
`
`Extrusion. A solution or particulate formulation is forced through holes to form microdroplets. High shear forces may damage proteins.
`Combining this technique with lyophilization may be a better choice because the cold, dry form is more stable, and the protein receives some
`protection from shear forces.
`
`Polymerization. Hydrogels, polymers that swell when they come into contact with water or an aqueous solvent, are mixed with the drug.
`Electromagnetic radiation forces chemical reactions that create a gel matrix to carry the drug.
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`Inhaled Biopharmaceuticals
`Offering an almost direct line to the circulatory system, alveoli in the lungs would be a good place to deliver proteins. However, because the lungs
`are a pathway for infections, the body's defense mechanisms make the alveoli hard to reach. Pulmonary delivery of polypeptides requires a
`device such as a nebulizer that makes an aerosol of the formulation (a liquid or a lyophilized powder) for inhalation. Only very tiny particles can
`reach far enough into the lungs for e(cid:168)cient drug delivery. The portion of the particle size spectrum generally considered able to penetrate
`farthest and deposit well into the lungs (<2-3 Âμm) is called the (cid:166)ne particle fraction (FPF). For biopharmaceutical drugs, a large portion of the
`device output should be 1-6 Âμm. Particle size distribution and weight determine how far into the progressively smaller lung pathways the drug
`will go. Heavier particles are deposited sooner, sometimes just at the back of the throat. If swallowed, the drug is wasted (see "The Oral Route"
`on Page 29).
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`Delivery by way of the respiratory system creates new stability issues. We know that protein structure determines bioactivity, and the generation
`of an aerosol for inhalation can subject a molecule to new modes of structural degradation. Metered-dose inhalers, familiar to asthmatics, don't
`work with biopharmaceuticals because of the harsh conditions they present to a formulation in the form of propellants and their mechanism of
`action. Some stabilizing excipients cannot be used for inhaled biopharmaceuticals because they may cause cough or bronchitis side effects,
`which may be dangerous as well as unpleasant for some patients. Formulation components cannot be allowed to interfere with aerosol
`generation, but the protein must be stabilized to survive the delivery process. Nebulizers expose a lot of the product's surface area for possible
`interactions, which must be minimized. If the delivery device is too customized, it may need to be approved through FDA's Center for Devices and
`Radiological Health as a medical device before the product's Biologics License Application can be approved. Patient factors (such as lung
`anatomy, breathing patterns, and possible pulmonary obstructions) can also affect the e(cid:168)ciency of delivery.
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`Four key questions are on the mind of a formulator developing a biopharmaceutical for inhalation:
`
`(1) How much drug will exit the device as an aerosol?
`
`(2) What is the size distribution of particles in the aerosol?
`
`(3) How reproducible is the aerosol generation process?
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`(4) How do the device and its aerosolization process affect the quality and e(cid:168)cacy of the drug formulation?
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`The (cid:166)rst three questions will be addressed by laser diffraction for nebulizer clouds. For the last question, characterization techniques (as used in
`preformulation) should be performed on the product that exits the device as well.
`
`Like parenteral drugs, inhaled biopharmaceuticals come in liquid and lyophilized forms. No matter which form the basic formulation takes, it will
`go through three main steps toward incorporation into the delivery device:
`
`Choose the device
`
`Choose excipients
`
`Determine related manufacturing issues.
`
`Step 1: Choosing the device. Various types of nebulizers use compressed gas (usually nitrogen because oxygen can degrade proteins) or sound
`waves to create droplets and force them out of the device. Potential degradation pathways include high concentrations and heat build-up with
`the ultrasonic method and product recirculation with the gas. Mechanical methods of extrusion through tiny holes can cause shear stress.
`
`Few multidose powder formulations are in development because of humidity and crystallization problems over time with the micronized (a
`process that reduces the particles to FPF size) particles. Unit-dose foil blister packs or "multidose" disks and tapes (really unit-dose multipacks)
`provide patient convenience. Unit-dose packaging (in blister packs) is usually preferred in liquid formulations because multidose products require
`preservatives. Complete sterility is not required for such products by US or EU regulatory authorities. Instead, inhaled biopharmaceuticals must
`conform to microbial limits measured in colony-forming units (cfu).
`
`Patients prefer hand-held nebulizers to larger, more complex devices. Most devices are patient-driven, but some companies are working on
`powered nebulizers. In this case, the choice depends more on delivery requirements than molecular characteristics. Because the digestive
`system is very adept at disassembling proteins, accidental swallowing of the product is avoided more for cost than safety.
`
`Step 2: Choosing the excipients. The drug indication matters — most asthmatics are sensitive to a range of excipients. Most buffers are known
`to cause coughing, an adverse reaction that can expel the drug, so no buffer can be used in an inhaled biopharmaceutical even though pH control
`is needed because degradation is often pH-dependent (>5 is best). At 1-6 Âμm, the dry particles of powdered formulations often act against each
`other, requiring excipients or carriers for the larger ones. Formulators must weigh (cid:167)ow and dispersal rates against each other to determine the
`optimal conditions for a given formulation.
`
`Multidose liquid formulations require preservatives that can interact with proteins to denature, aggregate, precipitate, or change their e(cid:168)cacy.
`Europe is stricter than the US on preservative use, citing that some preservatives can cause bronchoconstriction. Salt included as an isotonici(cid:166)er
`can interact with stainless steel storage of bulk formulations to cause metal-chelated oxidation. It may be helpful to add sugars, but some can
`cause bronchoconstriction.
`
`Step 3: Determining manufacturing issues. Small doses are better than large doses, so high concentrations (>50 mg/mL) are desirable for
`inhaled biopharmaceuticals if they don't lead to solubility or aggregation problems. Whereas asthma drugs are typically given by the microgram,
`many proteins are dosed by the milligram.
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`Logistics come into play if the biopharmaceutical company is partnering with a medical device company for its (cid:166)nal dosage form. Development
`of the bulk product formulation will have to take into account interim storage conditions and shipping to the device company that will load it into
`devices in a (cid:166)ll and (cid:166)nish operation. Preservatives or different stabilizers may be required, and sterility is always a concern for liquid
`formulations. Liquid formulations for pulmonary delivery are stored frozen (requiring freeze-thaw testing) or at a controlled temperature (typically
`2-8° C). Powder formulations are spray-dried or lyophilized and then micronized.
`
`The Oral Route
`
`Pills are sort of a Holy Grail for drug formulators, especially those involved with biopharmaceuticals. Many successful therapeutics are deliveredHoly
`to patients by way of a tablet, capsule, or pill. Oral delivery is preferable for several reasons, and patient compliance is near the top of the list.
`Patients are much happier swallowing a pill than getting an injection, using an inhaler, or spending time hooked up to an IV unit. Pills are also
`highly stable and typically have long shelf lives.
`
`So why are protein pills so di(cid:168)cult to develop? Our digestive systems evolved to do one thing well — break down food into usable raw materials.
`Proteins are some of the main nutrients we eat, so our gastrointestinal tract is pretty good at breaking them down.
`
`Built-in barriers to protein and peptide uptake by the oral route include enzymatic membrane mechanisms, protein biocompatibility, chemical
`breakdown, and physical clearance. Transport of the large molecules is controlled by enzymatic breakdown, particularly in the stomach and small
`intestines.
`
`Many research laboratories are working on oral delivery systems, speci(cid:166)cally protection against degradation and other approaches to oral
`delivery. For peptide or protein drugs to make it through the digestive system intact, they must be protected from enzymatic degradation and get
`into the bloodstream. They must be maintained at maximum solubility until they get to the intestines, where proteins are best absorbed into the
`bloodstream. Recall Ganderton's comment that even low bioavailability might be acceptable if it is reliable.
`
`Buccal delivery. Other companies are developing buccal delivery formulations for biopharmaceuticals. The drug is delivered to the body by way
`of the mucosal membranes, in this case those inside the mouth. Biopharmaceuticals may be incorporated into patches that stick to the roof of
`the mouth or underneath the tongue. Buccal delivery requires absorption enhancers.
`
`Other Delivery Methods
`Transmucosal drug delivery (including suppositories, which suffer from a poor reputation with patients) usually falls into the "miscellaneous"
`category of drug delivery technologies for therapeutic proteins, and only a few are in development. Several biopharmaceutical companies and
`companies that specialize in drug delivery are trying to create new methods of delivering large protein molecules to the body.
`
`Sometimes the method of delivery depends on the indication, as with intraocular drugs (those delivered through the mucosal membranes
`surrounding the eye) and topical formulations, such as Regranex Gel for treating diabetics' skin wounds.
`
`Nasal delivery. Doctors and patients want methods of drug delivery that are more convenient than parenterals. Nasal delivery is transmucosal
`delivery through the nose, which has good protective mechanisms for keeping proteins and infectious agents from crossing its mucosal barriers.
`For nasal delivery of biopharmaceuticals to be a viable therapeutic option, therefore, such mechanisms must be overcome, which may involve
`adding absorption enhancers. Even so, the nose offers low bioavailability (<5%) for proteins, but its mucosa are permeable to many peptides.
`Several peptide drugs are currently on the market as nasal drops or sprays. Sprays work best, but as with certain inhaled formulations, device
`development and manufacturing may become an issue. For patient compliance, sprays are preferable because nasal drops require special
`directions (to move the head in a particular way, for example), and the tickle causes many patients to sneeze.
`
`Nasal delivery requires larger particles than pulmonary delivery. Droplets <10 Âμm are so light they go right past the nose and into the respiratory
`tract. Also nasal dosages must be high to make up for the low bioavailability. Absorption enhancers are being studied to address this problem.
`
`Cellular implants. What if you could dispense with all the intermediate steps between cell-culture production of a therapeutic molecule and its
`delivery to the patient? In a process similar to creating drug microspheres for sustained parenteral or pulmonary delivery, genetically engineered
`cells (often human skin or epithelial cells) can be encapsulated in cellulose sulfate or another biopolymer. The encapsulated cells are then
`implanted under a patient's skin to form "neo-organs," which the body automatically provides with vascularization like it often does with tumors.
`But this tiny invader helps the body rather than harms it.
`
`The biopolymer encapsulation provides an immunoprotective barrier for the cells, allowing in only nutrients from the bloodstream and allowing
`out only pure cell-secreted protein with the typical cellular waste products the body handles all the time. The patient's body will not reject this
`"neo-organ" as foreign because there is no contact between its immune-response cells (such as T-cells) and the encapsulated cells.
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`The Blood-Brain Barrier
`To protect the brain from infection and from damage that could be caused by foreign chemicals, the endothelial cell linings of its capillaries are
`tightly packed together. Nothing but water can diffuse freely from the blood to the brain. Nutrients are actively transported by cellular
`mechanisms across the blood-brain barrier (BBB). Most drugs are treated as foreign material to be excluded from entering brain (cid:167)uids. Only a
`few drugs can enter the brain at all. Much of the time this is bene(cid:166)cial; many powerful drugs could cause trouble if they got past the BBB. But,
`what if the brain is already in trouble (it has a tumor, for example), and the drugs need to get into its (cid:167)uids to do their job?
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`Biopharmaceutical Drug Delivery
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`The Blood-Brain Barrier
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`Some drugs are chemically similar enough to brain nutrients (or can be made enough like them) that they can be moved into the brain by the
`nutrient back door. Water-soluble substances are almost universally excluded from the brain. But fat-soluble substances can dissolve across the
`membranes of endothelial cells and pass through them into the brain. So another method of getting a drug across the BBB is to make it lipid
`soluble. With a protein, that can be a tall order. And if those chemical methods won't work, there is currently only one other choice, and it can be
`risky.
`
`Highly concentrated sugar solutions, when injected into the arteries that supply the brain, will force the endothelial cells to shrink temporarily.
`That opens up gaps between them through which drugs injected immediately following can diffuse. Of course, anything else that happens to be
`going by in the bloodstream at that time may get across the BBB as well, and that makes this a risky approach. But sometimes — as in the
`treatment of brain tumors — the cure is worth the risk.
`
`Biopharmaceutical developers are used to thinking in such terms. The (cid:166)eld of risk assessment is about weighing the possible bene(cid:166)ts of a
`therapy or process step against its drawbacks. Meanwhile, product developers continue to work toward breaching the BBB. Some methods under
`study include facilitated diffusion; receptor- or carrier-mediated transport using glycoproteins, nucleosides, certain vitamins, iodine, or amino
`acids; and oligoglycerols.
`Related Content:
`
`Introduction and Acknowledgements
`
`Fill and Finish Operations
`
`Glossary
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