Parenteral Dosage Forms
Parenteral Dosage Forms
Parenteral dosage forms are a dosage form that break one's skin. These are in the form of injections. Because this is an injectable dosage form and it breaks the protective barrier of the skin, the product must be free of contamination. This would require some form of control over how these products are produced. The safety guidelines for production of compounded sterile products is under USP <797>. This is gives details and instructions on how to set up a sterile practicing environment, it breaks down various risk levels and how to best assess those, it talks about training in aseptic techniques, ways to perform quality control and how to assign storage and beyond-use-dates. Any practitioners who compound medications should abide by these regulations to ensure the quality of their dosage form and the safety of their patients. If a practitioner fails to comply with the guidelines proposed in USP <797> it is considered adultery seeing as the compounder knew about the document but applied willful neglect. Once guilty of adultery, the individual responsible can face jail time.
There are many advantages of given parenteral dosage forms. One is to ensure that the patient is getting the correct concentration of a drug. For example, based on a patient's weight, you determine that they need 18 g of a medication and that is not a strength that is manufactured normally. Compounding this into a parenteral dosage form would give the patient that exact dose. Parenteral dosage forms also ensure that patient's who cannot take medications via the oral route can get it in some other manner. Some patients have terrible mouth sores or are on a feeding tube in a hospital setting. In these situations, a parenteral dosage form would be ideal. A parenteral dosage form allows you to inject a medication directly to specific organ or tissue. With this, you don't have to wait for a tablet to dissolve and permeate membranes to get to its target site. You can inject a medication directly into the muscle, or in more severe cases, you can inject medication in the heart for example.
Despite these advantages, there are some disadvantages. One of the biggest ones is that once you inject this dosage form, you can't get the medication back. If there is something wrong with the medication, there is no way to recover it, making it one of the highest risk routes of administration associated with infection. Because of this, USP <797> outlines very important lab practices to be followed during the production of low-risk, medium-risk, and high-risk compounded products. Low-risk production includes the reconstitution of a single-use drug in a closed system without storage. Medium-risk production involves admixtures, pooling, and short-term storage. High-risk products involve the production of drugs using non-sterile ingredients, and they undergo long-term storage.
Other disadvantages include lack of so called "man power" and business perspectives. The FDA does not have nearly enough trained professionals to cover all compounding facilities and once again this can relate back to overall cost to supply such employees with an appropriate salary. While large manufacturers are most important to be checked for compliance with USP <797>, other smaller scale compounding facilities, such as community pharmacies are not regulated for such safety and efficacy. In addition, many companies may opt out of certain costly technologies and other needs that are deemed necessary in order to comply with USP <797>. While a CEO may think in terms of cost effectiveness, the healthcare professional is concerned with patient safety and product reliability. Without a strong case, the healthcare professional may be at a loss of means to fulfill such standards.
The cost of making parenteral dosage forms can be high. In addition, those administering the dosage form can make mistakes. There are cases when the needle is inserted through a vein into surrounding tissue. This can irritate or damage the surrounding tissue and reduce the distribution of the drug into systemic circulation.
Routes of Administration
There are three different routes of injection for parenterals: intravenous, intramuscular, and subcutaneous. Intravenous injections go directly into the blood through a major peripheral vein which leads to a 100% bioavalability because the drug is administered directly to the central compartment or blood. The drug is injected as a solution directly into the blood, so a response may be seen immediately since dissolution does not occur. Once the drug is in the blood it can then diffuse into the peripheral tissues or be eliminated from the body.
Within intravenous injections, there are three different routes of administration. These include: IV push, intermittent infusion, and constant infusion. An IV push or bolus dose is a small volume, single dose given over a short period of time. Initially when the dose is given the concentration of drug in the blood is high, but the concentration decreases in proportion to the rate of elimination of drug in the body. Bolus doses can be used for pain management and any other medications that you need to administer immediately. They are also useful if that patient already has an IV line and/or if the patient cannot take medicine orally. Intermittent infusions are multiple doses given over a short period of time repeatedly in order to keep the concentration of drug in the blood above the minimum effective level. Constant infusion is a single dose that is given continuously over a period time so that the concentration of drug in the blood remains constant.
Patient Controlled Analgesia (PCA) utilizes the different routes of administration of intravenous injections. In PCA, patients receive a constant dose of drug, usually morphine; however, if the drug concentration in the blood drops below the minimum effective level and the patient can now feel pain there is a button they can push on the PCA pump. Pressing this button administers a bolus dose of morphine to immediately alleviate pain. To prevent overdosing, there is a safety feature built into the pump, it only allows a certain amount of bolus doses to be administered in a given amount of time. PCA pumps are continuous infusion with patient controlled administration of bolus doses; however, if looking at the concentration of drug in the blood over time the profile will look more like an interment infusion.
Sustained Release Systems
One important branch of parenteral dosage forms are sustained release systems. Sustained release systems, or "depot systems" allow for prolonged delivery of a particular drug into the blood stream, meaning less injections are needed as drugs can remain in the body for months at a time. There are four primary types of sustained release systems:
1. Suspension/Emulsion Systems, 2. Implants, 3. Microparticles, and 4. In-Situ Forming Depot Systems.
(1) For suspension and emulsion systems, the drug release rate is based on solubility and viscosity. In general, aqueous solutions have the fastest release because of their higher solubility, while oil solutions will be a slower release because there is no dissolution event. At the far end, oil suspensions are the slowest because of their increased viscosity.
(2) Implants make use of either biodegradable or non-degradable systems to release the drug. Biodegradation occurs through surface erosion and bulk erosion. Surface erosion occurs on the surface of the polymer, allowing drug release as the surface decreases. In bulk erosion, water penetrates the matrix and forces drug release through pores; the drug gets smaller, more porous and fragmented. The important thing about biodegradation is the drug release rate is not solely based on Fick's Law of Diffusion; there are other factors at play (like the rate of erosion). Biodegradable polymers have cleavable groups that allow for degradation, with one of the most common being Polylactide-co-glycolide (PLGA) polymers. These biodegradable usually contain ester groups, which are cleavable under biological conditions by non-specific hydrolysis or acid/base hydrolysis. The rate of hydrolysis and drug release can be tailored and designed to fit specific drug delivery needs based on the molecular weight of the polymer, the ratio of polymers (in PLGA the ratio of polylactide to polyglycolide) to influence the rate of drug release). which Any non-biodegradable implants must be removed surgically.
(3) Microparticles are micron-sized biodegradable polymers that contain drug to be released in the body, and they are simply injected with a needle intramuscularly or subcutaneously. The drug is released from the microparticle by erosion and diffusion. The rate of release can be controlled by the polymer molecular weight, particle size, composition, drug to polymer ratio, polymer/co-polymer ratio, and the porosity of microparticles. The polymer is usually in an organic solvent, which contributes to various ways to manufacture microparticles. Usually they are precipitated from and O/W emulsion of W/O/W emulsion.
(4) In-Situ Forming Depot Systems form a solid depot after injection, a more patient friendly sustained release system than an implant. The polymer and drug are co-dissolved in a solvent, and upon injection, the polymer precipitates forming a depot' the depot then releases the drug. These In-situ forming depot systems include: thermoplastic pastes, in-situ polymer precipitation, thermally induced gelling systems, and in-situ cross-linked polymer systems. Thermally induced gelling systems (In-Situ) become a gel upon injection because of temperature. Drug is released from diffusion and polymer degradation at the site for up to 4 weeks similarly to other depot injections.
Tonicity and Osmotic Pressure
Tonicity is an important topic when we look to make parenteral products. As mentioned in the lecture, ideally an IV admixture is used in a solution that is isotonic to blood. The human body is made up of around 60 percent water so it is critical that tonicity is considered when making intravenous formulations. A drug solution that is hypertonic to blood could locally shrink cells and cause severe pain and problems administering the drugs where as hypotonic solutions can present problems as well causing cells to lysis and burst. As mentioned in PHCY 410, drugs that are hypotonic or hypertonic that must be administered should be done slowly to minimize the negative side effects, however; ideally we work to make drug admixtures in hospitals isotonic to blood when we intended to administer them in a parenteral fashion. Some of the most common modes of delivering near isotonic drugs into the body is by using normal saline (0.9% NaCl), 5% dextrose, and lactated ringers. Each of these roughly have a osmolarity of 270-300 mOsmol/L, which is on par with blood. The importance of which fluid you use in certain preparations is evident. Firstly, some drugs are much more stable in one or the other medium so it is important to note this when deciding how to administer a drug to a patient. Secondly, NaCl is an electrolyte and will display those properties when administered with a drug, where as dextrose is a non-electrolyte. Dextrose 5% can also act as a hypotonic solution as the dextrose is metabolized by the body. The lactate in lactated ringers are converted by the liver into bicarbonate, so this is an obvious consideration when developing an intravenous infusion and could be used when the patient needs increased levels of bicarbonate and should be avoided in patients whose blood pH is higher than 7.5 or if they have a severe liver disease and the lactate cannot be converted. Generally, drugs added to these isotonic solutions increase their tonicity. Different disease states and patient conditions can call for mixtures that are not isotonic to blood. In other cases many fluids used can be hypotonic or hypertonic and used in patient specific circumstances. Two common such fluids are 0.45% NaCl (hypotonic) and 10% dextrose (hypertonic). Another thing to notice when making an injectable product is the use of buffers when working to maintain these parenteral formulations. In addition to the tonicity and osmotic pressure issues when making parenteral products it is important to monitor the buffers used to make sure the product is safe for use in parenteral products. There are many different buffers that are effective in different ranges. Physiological pH in humans is a little over 7 so the most effective buffer used in formulations for humans is phosphoric acid or phosphate. These buffers are usually considered safe in formulations when it is used in the 2-30 mM range. This issue of pH is very important because even with buffer systems in the body in place, if the pH of the formulation is much higher or lower than physiological pH it can produce hazards to the body. With all of these parameters to consider it makes it very difficult to make drug formulations that adhere to these specific requirements. 
Maintaining Product Stability
In designing a drug formulation, there are several important facotrs that need to be considered to maintain the stability of the drug. Some factors that might affect the chemical and physical properties of drugs are pH, oxidation, and microbial contamination. There are some ways that drug manufacturers used to maintain drug stability, such as adding buffers, antimicrobial preservatives, and antioxidants into the formulation.
Many pharmaceutical products in the market are acids or bases. Therefore, it is very important to understand the pH-solubility profile and acid/base catalysis of drug to ensure sufficient bioavailibility. There are different buffers available that have different pH range and can be used to maintain a particular pH condition for different drug formulation. Most parenteral products typically use phosphate buffer as it has a pKa similar to the pH of blood. However, phosphate might not be suitable for freeze-dry products since it will crystallize during the freezing process. Other components that need to be added into the formulation are antimicrobial preservatives and antioxidants. Microbes can be found everywhere and it is important to maintain pharmaceutical products sterility, especially when they are packaged for multiple-dosing use. Drug can also be exposed to oxidation, in which free radicals from oxygen cause degradation of drug stability. This problem can be resolved by adding antioxidants into the formulation. Antioxidants function as either free radicals acceptors or being preferentially oxidized versus the drug.
In addition to adding several components to the drug formulation, many products undergo freezing-drying (lyophilization) process to increase stability. Some drugs are not very stable in aquesous forms and they are converted into powder forms to maintain stability. Lyophilization is a process in which a pharmaceutical solution undergo sublimation after it is frozen. The process occurs when the temperature and pressure are below the eutectic point of water. The advantages of utilizing the lyophilization process is that the pharmaceutical products will have a long-term stability of the original dosage form. They can also be reconstituted at a shorter time. However, specialized equipments are needed and the total operation cost is expensive.
Preparation of Sterile Injectables
As emphasized above, it is very important that the parental dosage forms our patients are receiving are sterile and safe. Multiple methods have been developed to remove microorganisms from compounded drugs. Depending on the specific dosage form being sterilized, different sterilization methods can be implemented. Dry Heat Sterilization is a method that utilizes conduction to transfer heat from the surface of a substance inward. The high temperatures, up to 250 degrees Celsius, destroy microorganisms by dehydrating cells and oxidizing the constituents of cells. Various cycle temperatures and durations can be used, but lower temperatures require longer time periods to effectively sterilize the product. Different heat sources can be utilized to create the dry-heat necessary, but in the case of parenterals, most commonly used are hot air ovens. Dry Heat Sterilization is often used because it is simple and cost effective. Because the process uses such high temperatures, it is limited in the fact that it cannot be used to sterilize heat-labile substances. Dry Heat Sterilization is used for thermostable drugs, including dry powders, suspensions of drug in non-aqueous solvents, oils, fats, waxes, implants, and ophthalmic ointments.
Another method, also utilizing heat, is Steam Sterilization, also referred to as autoclaving. This process implements hot steam under pressures of 2-3 atmospheres to coagulate the cellular proteins of microorganisms. The presence of moisture allows proteins to denature at lower temperatures. The autoclave uses temperatures around about 130 degrees Celsius, which is noticably lower than those temperatures used in the Dry Heat method. Different autoclaves use two different air removal methods: gravity-displacement and dynamic-air-removal. With gravity-displacement, residual air leaves the cycle through a vent as steam enters the chamber. Conversely, in the dynamic-air-removal machine, air is removed from the autoclave chamber by means of pressure via a vacuum. Cycles consisting of higher temperatures for a shorter time period are used in "flash sterilization," and are used when an item is needed for immediate use. Steam sterilization is useful when you need to sterilize large volumes in a small period of time. This method, however, cannot be used to sterilize oil-based, moisture-sensitive, or heat-sensitive products.
Unlike the two methods discussed above, Filtration physically removes microorganisms using bacteria-retentive filters, using an exclusion principle based on size. One can choose filter membranes with varying pore sizes, but on average pore sizes are around 0.2 microns. A major advantage to this method is that filtering can be used to sterilize heat-sensitive products. Crucial to Filtration, is testing the integrity of the filter membranes. Different tests can be employed, but most commonly used is the Bubble Test, in which pressure is employed to a wet membrane. If bubbles are produced at pressures below the "bubble point pressure" set by the manufacturers, then the membrane has lost its integrity. Selecting the appropriate filter for a specific drug compound is also important. The filter must be both physically and chemically compatible. Using filters, one can also alter the flow rate, which can be an important factor when considering exposure time to the environment.
Gas Sterilization is a method often used to sterilize powders, plastics/polymers, vaginal inserts, plastic syringes, and tubing sets. The method uses ethylene oxide at 30 PSI at 20-55 degrees Celsius. Ethylene oxide sterilization requires three steps: pre-conditioning, sterilizer, and degasser. In the pre-conditioning step, microorganisms are allowed to grow for a certain amount of time under controlled temperature and humidity. Next, there is a 60-hour sterilizing cycle, the gas is released and sterilization occurs. There are constant environmental checks to make sure sterilization is occurring. Once sterilization is complete, degassing occurs, and all of the ethylene oxide is removed from the chamber. Although this method is useful in sterilizing thermo-labile products, Gas Sterilization has major disadvantages. Ethylene oxide is a prolific alkylating agent, and if any excess remains in a drug product, it could damage human cells as well. The chemical is also extremely flammable, so the entire process has to be heavily monitored for temperature and pressure changes. Recently, research has been done to find an alternative gas that could be used with comparable efficacy.
By exposing ionizing radiation in the form of beta, gamma, X-rays or electrons via an accelerator to a material, food, or drug product, one can achieve Radiation Sterilization. This method is high penetrating and dubbed "terminal sterilization." In this method, high-energy waves damage the protein and genomic DNA of microorganisms. Depending on the size and properties of the batch of products being sterilized, different doses of radiation would be applied. Although this method is very effective at destroying microorganisms, radiation can detrimentally alter the drug product that you are sterilizing. Using radiation is also costly, requiring highly specialized equipment. It is clear that the five methods discuss vary greatly, and all have clear advantages and disadvantages.
USP Sterility Testing
There are two methods of conducting the USP 71 Sterility Test: direct inoculation of the medium and membrane filtration. Direct inoculation of the medium involves placing a sample of the product directly into a Fluid Thioglycollate Medium. This method requires less volume to conduct than the membrane filtration method and provides a means of sterility testing for materials that cannot be filtered, such as solids or ointments. However, this method cannot be used with any products that exhibit antimicrobial activity which may inhibit the growth of microbes in the medium. The other option for sterility testing is the membrane filtration test. The test compound is filtered through a membrane which is then incubated in a Fluid Thioglycollate Medium in lieu of incubating the compound itself. This allows larger volumes to be tested without dilution of the medium. In addition, the membrane can be used to filter drugs that have antimicrobial activity and rinsed following filtration to eliminate any antimicrobial effects of the compound itself. For both the membrane filtration and direct inoculation tests, the Fluid Thioglycollate Medium must be incubated for 14 days and assessed for bacterial growth. The presence of turbidity in the medium indicates a failed sterility test. 
Even though USP sterility testing is conducted to ensure sterility, however, it is not a fail-proof method. In order to confirm the absence of microorganisms contamination, the manufacturing process of sterile pharmaceutical products must be validated. The validation method utilizes a specific biological indicator, which is a microorganism that is resistant to a particular sterilization process. For instance, B. Stearothermophilus is resistant specifically to the steam and gas sterilization methods, B. Subtilis to the dry heat sterilization, B. Pumilus to the radiation sterilization, and P. Diminuta to the filtration sterilization. To validate the sterilization processes, the biological indicator is either included in the sterilization procedure or added in to the pharmaceutical products. At the end of the process, the prodcuts will be tested for the biological indicators. If the products are found to be free (below a defined threshold) of the indicator, the sterility of the process will be valid.
Small Volume Parenterals (SVPs) are less than 100 mL. They contain antibacterial preservatives, buffers, solubilizers, antioxidants, and other pharmaceutical additives/excipients. SVPs tend to be compounded dosage forms or products that are more novel in nature. Some examples include aqueous or non-aqueous solutions, suspensions, emulsions, and lyophilized powders. In contrast, Large Volume Parenterals (LVPs) are greater than or equal to 100 mL and administered by intravenous infusion. LVPs are for fluid replacement, electrolyte-balance restoration, and total nutrition. In contrast to SVPs, LVPs must not contain bariostatic agents or other pharmaceutical additives except the basic necessary ingredients. Examples of LVPs are dextrose injection 5% USP, mannitol injection USP, and ringers injection USP.
In general, basic characteristics of parenteral products are sterile, pyrogen-free, particle-free, stable, isotonic, and safety. All of these characteristics are enhanced and ensured by following proper sterile procedures in the preparation of these products.