2 Lecture 3 Sterile products dosage.pdf

OVERVIEW OF PRODUCT DEVELOPMENT 8 General guidance for developing formulations of parenteral drugs The final formulation of a parenteral drug product depends on understanding the following factors that dictate the choice of formulation and dosage form. Route of Administration In...

OVERVIEW OF PRODUCT DEVELOPMENT 8 General guidance for developing formulations of parenteral drugs The final formulation of a parenteral drug product depends on understanding the following factors that dictate the choice of formulation and dosage form. Route of Administration Injections may be administered by such routes as intravenous, subcutaneous, intradermal, intramuscular, intra-articular, and intrathecal (chap. 31). The type of dosage form (solution, suspension, etc.) will determine the particular route of administration that may be employed. Conversely, the desired route of administration will place requirements on the formulation. For example, suspensions would not be administered directly into the bloodstream because of the danger of insoluble particles blocking capillaries. H o w e v e r, n a n o s u s p e n s io n s ca n b e d e l i v e re d di r e c t l y t o t h e b l o o d s t r e a m. Solutions to be administered subcutaneously require strict attention to tonicity adjustment; otherwise irritation of the plentiful supply of nerve endings in this anatomical area would give rise to pronounced pain. Injections intended for intraocular, intraspinal, intracisternal, and intrathecal administration require stricter standards of such properties as formulation tonicity, component purity, and safety because of the sensitivity of tissues encountered to irritant and toxic substances. If the route of administration must be intravenous, then only solutions, microemulsions or nanosuspensions can be the dosage form. Pharmacokinetics of the Drug Rates of absorption (for routes of administration other than intravenous or intra-arterial), distribution, metabolism, and excretion for a drug will have some effect on the selected route of administration and, accordingly, the type of formulation. For example, if the pharmacokinetic profile of a drug is very rapid, modified release dosage formulations may need to be developed. The dose of drug and the dosage regimen are affected by pharmacokinetics, so the size (i.e., concentration) of the dose will also influence the type of formulation and amounts of other ingredients in the formulation. If the dosage regimen requires frequent injections, then a multiple dose formulation must be developed, if feasible. If the drug is distributed quickly from the injection site, complexing agents or viscosity-inducing agents may be added to the formulation to retard drug dissolution and transport. Drug Solubility If the drug is insufficiently soluble in water at the required dosage, then the formulation must contain a cosolvent or a solute that sufficiently increases and maintains the drug in solution. If relatively simple formulation additives do not result in a solution, then a dispersed system dosage form must be developed. Solubility also dictates the concentration of the drug in the dosage form. Figure 5 presents a schematic decision tree that formulation scientists typically follow in overcoming drug-solubility problems for drugs intended for IV administration, and this will be further elaborated. Basically, the approaches used to overcome solubility problems start first with the drug itself (salt formation), then simple approaches with the formulation (pH adjustment, addition of cosolvent, complexing agent, and/or surface-active agent), and, if none of these produce the desired result, the last approach is to change the dosage form to a dispersed system or other more complicated formulation.  STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY Drug Stability If the drug has significant degradation problems in solution, then a freeze dried or other sterile solid dosage form must be developed. Stability is sometimes affected by drug concentration, which, in turn, might affect the size and type of packaging system used. For example, if con- centration must be low due to stability and/or solubility limitations, then the size of primary container must be larger and this might preclude the use of syringes, cartridges, and/or smaller vial sizes. Obviously, stability dictates the expiration date of the product, which, in turn, will determine the storage conditions. Storage conditions might dictate the choice of container size, formulation components, and type of container. If a product must be refrigerated, then the container cannot be too large and formulation components must be soluble and stable at colder conditions. Achieving drug stability is overall the number one reason for adding solutes to an injectable formulation and subsequent chapters on formulation of solutions, dispersed systems,and freeze-dried products will show this emphasis. Compatibility of Drug with Potential Formulation Additives It is well known that drug-excipient incompatibilities frequently exist and these will be pointed out in subsequent chapters. Initial preformulation screening studies are essential to assure that formulation additives, while possibly solving one problem, will not create another. Stabilizers, such as buffers and antioxidants, while chemically stabilizing the drug in one way, may also catalyze other chemical degradation reactions. Excipients and certain drugs can form insoluble complexes. Impurities in excipients can cause drug degradation reactions. Peroxide impurities in polymers may catalyze oxidative degradation reactions with drugs, including proteins, that are oxygen sensitive. Desired Type of Packaging Selection of packaging (type, size, shape, color of rubber closure, label, and aluminum cap) often is based on marketing preferences and competition. Knowing the type of final package early in the development process aids the formulation scientist in being sure that the product formulation will be compatible and elegant in that packaging system. Tables 5 provide different views of the steps and tasks involved in the formulation of a new parenteral drug product. This information can also be viewed as a list of questions, the answers of which will facilitate decisions on the final formulation that should be developed. Formulation Principles Parenteral drugs are formulated as solutions, suspensions, emulsions, liposomes, microspheres, nanosystems, and powders to be reconstituted as solutions. Each dosage form is formulated dif- ferently, although formulation components besides the active ingredient are added only when absolutely necessary. In other words, ideally, a formulation will contain active ingredient and water with no added substances. While this is true for high-dose products such as cephalosporin antibiotics, the large majority of parenteral drug products do contain added substances. Nevertheless, it is always the goal of a formulator of a sterile drug product to keep that formulation as simple as possible with a minimum of added substances (excipients).  STERILE DRUG PRODUCTS: FORMULATION Table 5 Main Steps Involved in the Formulation of a New Sterile Drug Product 1. Obtain physical properties of active drug substance a. Structure, molecular weight b. “Practical” solubility in water at room temperature c. Effect of pH on solubility d. Solubility in certain other solvents e. Unusual solubility properties f. Isoelectric point for a protein or peptide g. Hygroscopicity h. Potential for water or other solvent loss i. Aggregation potential for protein or peptide 2. Obtain chemical properties of active drug substance a. Must have a “validatable” analytical method for potency and purity b. Time for 10% degradation at room temperature in aqueous solution in the pH range of anticipated use c. Time for 10% degradation at 5◦ C d. pH stability profile e. Sensitivity to oxygen f. Sensitivity to light g. Major routes of degradation and degradation products 3. Initial formulation approaches a. Know timeline(s) for drug product b. Know how drug product will be used in the clinic i. Single dose vs. multiple dose ii. If multiple dose, will preservative agent be part of drug solution/powder or part of diluent? iii. Shelf-life goals iv. Combination with other products, diluents c. From knowledge of solubility and stability properties and information from anticipated clinical use formulate drug with components and solution properties that are known to be successful at dealing with these issues. Then perform accelerated stability studies i. High-temperature storage ii. Temperature cycling iii. Light and/or oxygen exposure iv. For powders, expose to high humidities d. May need to perform several short-term stability studies, as excipient types and combinations are eliminated e. Understand need for any special container and closure requirements f. Design and implement an initial manufacturing method of the product g. Finalize formulation i. Need for tonicity adjusting agent ii. Need for antimicrobial preservative h. Approach to obtain sterile product i. Terminal sterilization ii. Sterile filtration and aseptic processing  STERILE DRUG PRODUCTS: FORMULATION PACKAGING, MANUFACTURING, AND QUALITY PARENTERAL DOSAGE FORMS Solutions Most injectable products are solutions. Solutions of drugs suitable for parenteral administration are referred to as injections. Solutions can be either aqueous or nonaqueous (called oleaginous solutions). Aqueous solutions can be completely water based or water combined with a water-miscible organic cosolvent such as ethanol, polyethylene glycol, glycerin, or propylene glycol. Nonaqueous solutions, also called oleaginous solutions, contain oils as the vehicle. Only oils of vegetable origin are acceptable for injectable products, the most common oils being soybean, sesame, and cottonseed. Oily solutions must not be administered by the IV route. Many injectable solutions are manufactured by dissolving the drug and any excipients, adjusting the pH, sterile filtering the resultant solution through a 0.22μm membrane filter, and, when possible, autoclaving the final product. Most solutions have a viscosity and surface tension very similar to water. Sterile filtration, with subsequent aseptic filling, is common because of the heat sensitivity of many drugs. Those drug solutions that can withstand heat should be terminally autoclave sterilized after filling, since this best assures product sterility. Injections and infusion fluids must be manufactured in a manner that will minimize or eliminate extraneous particulate matter. A l l parenteral solutions are filtered to remove particulate matter. The total fluid volume that must be filled into a unit parenteral container is typically greater than the volume that would contain the exact labeled volume. The fill volume is dependent on the viscosity of the solution and the retention of the solution by the container and stopper. The USP provides a procedure for calculating the fill dose that is necessary to ensure the delivery of the stated dose. It also provides a table of excess volumes that are usually sufficient to permit withdrawal and administration of the labeled volume. Suspensions One of the most difficult parenteral dosage forms to formulate is a suspension. It requires a delicate balance of variables to formulate a product that is easily resuspended and can be ejected through an 18 to 21 gauge needle through its shelf life. To achieve these properties, it is necessary to select and carefully maintain particle size distribution, zeta potential, and rheological properties, as well as the manufacturing steps that control wettability and surface tension. The majority of injectable suspensions are aqueous-based (drug dispersed in an aqueous vehicle). Suspensions formulated with an oily vehicle include bovine somatotropin (bST) in sesame oil and a long-acting parenteral suspension of adrenocorticotropic hormone (ACTH) that is also formulated in sesame oil. Suspensions are usually developed when (i) sustained release is desired as well as when (ii) the drug stability and potency is better in solid suspended form.  STERILE DRUG PRODUCTS: FORMULATION A formula for an injectable suspension usually consist of the active ingredient suspended in an aqueous vehicle containing a surfactant for wetting, a dispersing or suspending agent, and perhaps a buffer and an antimicrobial preservative if needed. Two basic methods are used to prepare parenteral suspensions: (i) sterile vehicle and powder are combined aseptically (aseptic sterile powder addition) or (ii) sterile solutions are combined and the crystals formed in situ (in situ sterile crystallization). Example of the first method is the production of penicillin G procaine injectable suspension USP. An example of the second method is sterile testosterone injectable suspension USP. Selecting the appropriate preparation method is very critical. If the drug can be crystallized, then a crystalline suspension can be prepared that offers several advantages over an amorphous suspension. A main advantage of preparing crystals for pharmaceutical suspensions is the fact that a suspension composed of these crystals will likely have desirable pharmaceutical properties such as resuspendability, syringeability, and injectability. Successful, reproducible drug crystallization is significantly dependent on drug substance purity since impurities will likely influence the crystallization outcome. The critical nature of the flow properties of parenteral suspensions becomes apparent when one remembers that these products are frequently administered through 1 in. or longer needles having internal diameters in the range of only 300 to 600 μm. The flow properties of parenteral suspensions are usually characterized on the basis of syringeability and injectability. The term “syringeability” refers to the handling characteristics of a suspension while drawing it into and manipulating it in a syringe. Syringeability includes characteristics such as ease of withdrawal from the container into the syringe, clogging and foaming tendencies, and accuracy of dose measurement. The term “injectability” refers to the properties of the suspension during injection; it includes such factors as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging. The syringeability and injectability characteristics of a suspension are closely related to viscosity and particle characteristics. Special tests for quality control evaluation of parenteral suspensions are usuallyfocused on the syringeability and injectability properties hence the syringeability and injectability test is performed. As mentioned earlier both the particle size and rheological properties can hugely affect the parenteral suspensions properties. Therefore, quality control tests to accurately monitor the particle size and particle size distribution as well as the rheological properties must be done. Emulsions An emulsion is a dispersion of one immiscible liquid in another. This inherently unstable system is made possible through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Globule size for emulsions can range from 0.1 to 50 μm with emulsions administered by intravenous injection or infusion needing to  STERILE DRUG PRODUCTS: FORMULATION PACKAGING, MANUFACTURING, AND QUALITY be of globule size less than 1 μm. Parenteral emulsions have been used for several purposes, including (i) long-term parenteral nutrition (given by IV infusion), (ii) o/w sustained-release depot preparations (given intramuscularly) and (iii) alternative dosage forms for poorly water-soluble drugs with high log P (good lipid solubility). Parenteral emulsion formulation are severely restricted through a very limited selection of oils and emulsifiers. Oils usually used are winterized vegetable oils (e.g., soybean oil and sunflower oil). Triglycerides can also be used specially medium and long chain triglycerides. The emulsifier of choice is egg yolk phospholipid which is chromatographically purified prior to use. Auxiliary emulsifiers like polyethylene glycols are usually added to parenteral emulsions. Stabilizers, buffers and antioxidants are integral additives to parenteral emulsion to maintain its stability and prevent the formation of free fatty acids and oxidation of oils, respectively. Table 3 shows some of IV Fat emulsions compositions. Emulsion manufacture consists of dispersing the oil phase and all dissolved components into the aqueous phase with its dissolved components by the use of high shear equipment such as colloid mills, ultrasonifiers, and homogenizers. There are special tests for quality control evaluation of parenteral emulsions: Determination of the fat globule size Determination of phase separation Determination of viscosity Dry Powders Many drugs are too unstable—physically or chemically—in an aqueous medium (hydrolysable drugs) to allow formulation as a solution, suspension, or emulsion. Instead, the drug is formulated as a dry powder that is reconstituted by addition of water before administration. The reconstituted product is usually an aqueous solution; however, occasionally it may be an aqueous suspension (e.g., ampicillin trihydrate and spectinomycin hydrochloride are sterile powders that are reconstituted to form a sterile suspension). Dry powders for reconstitution as an injectable product may be produced by several methods, the most common is filling the product into vials as a liquid and freeze-drying. The reason most sterile solids are prepared by lyophilization is the fact that liquid filling presents less problems than powder filling and for powder filling the product needs to be crystalline in solid state character. Amorphous solids are very difficult to fill accurately because of their relative lack of density (too fluffy).  STERILE DRUG PRODUCTS: FORMULATION Table 3 IV Fat Emulsions Composition in % (w/v) Component (g/100 mL) Intralipida Liposyn IIb Infonutrolc Lipofundind Liphysane 10% 20% 10% 20% 10% 20% 10% 10% 15% Soybean oil 10 20 5 10 Safflower oil 5 10 Cottonseed oil 15 10 10 15 Egg 1.2 1.2 1.2 1.2 phospholipids Egg 1.2 1.2 phospholipids Egg 1.5 2 phospholipids Glycerol 2.25 2.25 2.25 2.25 Glucose 4 Cholesterol 5 5 5 piuronic F-68 0.3 DL-αTocopherol 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 WFI, q.s. 100 mL 100 mL 100 mL 100 100 mL mL a Kabi-Vitrum A.G., Stockolm, Sweden. b Abbott Laboratories, North Chicago, Illinois, U.S. c Astra-Hewlett, Sodertaye, Sweden. d Braun, Melsunger, West Germany. e Egic, L, Equilibre Biologique S.A., Loiret, France. Abbreviations: IV, intravenous; WFI, water for injection.  Advanced parenteral drug delivery systems (A) (B) (C) (D) Figure 3-1 Examples of injectable dosage forms. (A) Solution. Source: Courtesy of Baxter Healthcare Cor- poration. (B) Suspension. Source: Courtesy of Dr. Gregory Sacha, Baxter. (C) Lyophilized powder (GemzarⒸR ). Source: Courtesy of Eli Lilly and Company. (D) Emulsion. Source: Courtesy of Teva Pharmaceuticals  Advanced parenteral drug delivery systems The focus on developing advanced parenteral drug delivery systems is to achieve mainly two goals: first to maintain a highly controlled drug release profiles, second target drug(s) to the desired site of action. By achieving the first goal this will help reducing the total number of injections throughout the drug therapy period therefore improve patient compliance. As for the second goal, it will help improving the effectiveness and reducing the undesirable effects of the active ingredient. These goals are achieved by developing novel depot delivery systems. The early depot systems included suspensions and emulsions. While, nowadays the depot delivery systems include: A- Implants B- Microspheres C- Injectable gels D- Phospholipid based systems E- Nanosuspensions A- Implants: Implants are formed either formed of biodegradable polymers (hydrolytic degradation) or non-biodegradable polymers. Our focus in the upcoming section will be on biodegradable implants. Implants can be implanted either by using certain type of needles (injectable implant) or during surgical operations (surgical implants). I- Injectable implant Injectable implants are usually injected subcutaneously to release active ingredient from weeks to several months. Goseraline acetate implant (Zoladex®) is one of the most famous injectable implant. Zoladex® consisted of goseralin acetate as the active ingredient dispersed in a polymeric matrix of D, L- lactic & glycolic acid copolymer. Zoladex® is injected SC to release drug from one up to three months.  Advanced parenteral drug delivery systems It is used in the treatment of prostate and breast cancer. of brain tumors. B- Microspheres Microspheres designed for parenteral delivery, are injected using conventional needles and syringes. Thus, they have been the most widely accepted biodegradable polymer system for parenteral uses. PLGA microspheres PLGA microspheres are by far the most commonly used polymer-based injectable depot drug delivery systems. PLGA is a biodegradable polymer of polyesters of poly (lactic - co - glycolic acids). They have the following advantages: Biocompatible, Easily administered through conventional needles and syringes, Provide sustained release for prolonged time, Encapsulate active molecules with wide-ranging physicochemical properties, including small molecules, peptides, proteins and nucleic acids. C- Injectable gels (Atrigel) This system consists of insoluble biodegradable polymers dissolved in a biocompatible solvent. The drug is added to this solution where it dissolves or forms a suspension. When this liquid drug/polymer system is placed in the body using standard needles and syringes, it solidifies upon contact with aqueous body fluids to form gel. When the polymer matrix solidifies, the drug incorporated into the polymer solution becomes entrapped. Hence, drug release will occur over a prolonged time as the polymer biodegrades. The most important advantages of Atrigel systems are: a) They can release drug(s) for a very prolonged time (up to six month), b) Compatibility with a wide range of pharmaceutical compounds: water soluble or insoluble compounds, high and low molecular weight compounds like peptides and proteins, vaccines and natural products, c) Easily administered: by using conventional needles and syringes. Eligard® is an in situ forming gel administered SC. It consists of leuprolide acetate as active ingredient contained in Atrigel polymeric in situ gel matrix delivery system. Eligard® is used for the treatment of prostate cancer. This system can deliver drug from one month up to six months.  Advanced parenteral drug delivery systems D- Phospholipid based systems I- Liposomes Liposomes are small, spherical vesicles consist of phospholipids bilayers (similar to those found in biological membranes) enclosing an aqueous core. Liposomes are categorizes according to the size and number of lamella (concentric bilayer membrane around the aqueous core) into: Small unilamellar vesicles (SUVs): having one bilayer membrane with diameter ranging from 20 - 100 nm. Large unilamellar vesicles (LUVs): having one bilayer membrane with diameter ranging from 100 - 400 nm. Giant unilamellar vesicles (GUVs): having one bilayer membrane with diameter exceeding 1 µm. Multilamellar vesicles (MLVs): have more than one concentric lamella with diameter ranging from 100 - 1000 nm. Liposomal drug delivery systems can be used either as targeted and/or sustained delivery. Currently two liposomal formulations approved by the FDA: 1) AmBisome®, a liposomal formulation of amphotericin B (antifungal) for intravenous infusion. 2) Doxil®, a liposomal formulation of doxorubicin (anticancer) used in the treatment of ovarian cancer. It is injected into a vein over 30-60 minutes. This system can deliver drug up to 28 days. E- Nanosuspensions Nanosuspensions are a colloidal dispersion of nano-sized drug particles dispersed in an aqueous vehicle. Nanosuspensions are used to formulate drugs that are poorly water soluble as well as poorly lipid or organic solvent soluble. Nanosuspensions are used for IV injections as drug(s) particles are in the nano-size. Abraxane® is a nanosuspension that has been recently approved by the FDA for IV administration. Abraxane® is a nanosuspension of Paclitaxel (a very water-insoluble anticancer agent) used in treatment of breast cancer. This system can deliver drug from one week up to three weeks.