Parenteral Components PDF

STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY 6 Formulation components (solvents and solutes) Sterile formulations, by necessity, must be as simple as possible. Safety considerations limit the number and choices of additives to use in f...

STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY 6 Formulation components (solvents and solutes) Sterile formulations, by necessity, must be as simple as possible. Safety considerations limit the number and choices of additives to use in formulations besides the active and, if stability is sufficient, a vehicle. The ideal parenteral formulation would contain the active ingredient, vehicle and a suitable container and nothing else. This chapter will describe the types and purposes of additives (adjuvants, excipients or non- active ingredients) and vehicles used in sterile formulations. References 1 through 8 provide reviews and listings of approved additives in marketed sterile product formulations including a valuable Food and Drug Administration Web site. Care must be taken in selecting active pharmaceutical ingredients and excipients to ensure that their quality is suitable for parenteral administration. A low microbial level will enhance the effectiveness of either the aseptic or terminal sterilization process used for the drug product. Likewise, nonpyrogenic ingredients enhance the nonpyrogenicity of the finished injectable product. It is now a common GMP procedure to establish microbial and endotoxin limits on active pharmaceutical ingredients and most excipients. For that, all ingredients used in parenteral preparations are of “parenteral grade” (very high purity). VEHICLES (SOLVENTS) The solvent in injectable formulations typically is the largest component. Of course, the preferred solvent or vehicle is water for injection (WFI). For drugs that are not sufficiently soluble in water, water-miscible organic co-solvents may be used with limitations on the acceptable amounts from a safety viewpoint. For drugs completely insoluble in water and not required to be injected intravenously, oily (oleaginous) solvent systems of vegetable origin may be used. Water Since most liquid injections are quite dilute, the component present in the highest proportion is the vehicle. The vehicle of greatest importance for sterile products is water. Water of suitable quality for compounding and rinsing product contact surfaces may be prepared either by distillation or by reverse osmosis, to meet United States Pharmacopeia (USP) specifications for WFI. Specification for WFI as per USP 1) Description → Clear, colorless and odorless liquid. 2) Microbial limitations a. Nonpathogens → Less than 10 cfu / 100mL. b. Pathogens → Should be absent. c. Bacterial endotoxins → Should be absent. 3) pH → Between 5.0 and 7.0 4) Total dissolved solids → Less than 10 ppm. WFI must be stored at either 5oC or 80oC with constant circulation (not stagnant). Therefore, WFI is stored in stainless steel tanks containing coils for cooling or heating and a circulating fans.  FORMULATION COMPONENTS (SOLVENTS AND SOLUTES) Sterile Water for Injection It is water for injection, which is sterilized usually by heat sterilization (steam sterilization) and does not contain any antimicrobial agent or any other substance. Bacteriostatic Water for Injection Addition of 1 or 2 antimicrobial agents to sterile water for injection results in bacteriostatic water for injection. Make sure that the antimicrobial agent is compatible with the API(s) which will be added in future. Sterile WFI and Bacteriostatic WFI are used for making parenteral preparations done under aseptic conditions for unit dose and multi dose preparations respectively. WFI is used for making parenteral preparations subjected to terminal sterilization. Water-Miscible Co-Solvents A number of solvents that are miscible with water have been used as a portion of the vehicle in the formulation of parenterals. These solvents are used primarily to solubilize certain drugs in an aqueous vehicle and to reduce hydrolysis. The most important solvents in this group are ethyl alcohol, liquid polyethylene glycol, and propylene glycol. Ethyl alcohol is used particularly in the preparation of solutions of cardiac glycosides and the glycols in solutions of barbiturates, certain alkaloids, and certain antibiotics. Several references provide information on concentrations of co-solvents used in approved commercial parenteral products. Nonaqueous Vehicles Oily vehicles cannot be administered by the intravenous route. The most important group of nonaqueous vehicles is the fixed oils. The USP provides specifications for such vehicles, indicating that the fixed oils must be of vegetable origin so that they will be metabolized, will be liquid at room temperature, and will not become rancid readily. The USP also specifies limits for the free fatty acid content, iodine value, and saponification value (oil heated with alkali to produce soap, i.e., alcohol plus acid salt). The oils most commonly used are corn oil, cottonseed oil, peanut oil, and sesame oil. Fixed oils are used particularly as vehicles for certain hormones (e.g., progesterone, testosterone, deoxycorticicosterone) and vitamin (e.g., Vitamin K, Vitamin E) preparations. The label must state the name of the vehicle so that the user may beware in case of known sensitivity or other reactions to it.  STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY ADDED SUBSTANCES The USP includes in this category all substances added to a preparation to improve products quality, maintain stability, ensure sterility, and aid in parenteral administration but not to give a pharmacological action. An added substance may  Increase and maintain drug solubility. Examples include co- solvents, complexing agents and surface active agents. The most commonly used complexing agents are the cyclodextrins, including Captisol®R. The most commonly used surface-active agents are polyoxyethylene sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitans monooleate (Tween 80).  Provide patient comfort by reducing pain and tissue irritation, as do substances added to make a solution isotonic or near physiological pH. Common tonicity adjusters are sodium chloride, dextrose, and glycerin.  Enhance the chemical stability of a solution, as do antioxidants, inert gases, chelating agents, and buffers.  Enhance the chemical and physical stability of a freeze-dried product, as do cryoprotectants and lyoprotectants.  Enhance the physical stability of proteins by minimizing self-aggregation or interfacial induced aggregation. Surface-active agents serve nicely in this capacity.  Minimize protein interaction with inert surfaces such as glass and rubber and plastic. Competitive binders such as albumin and surface-active agents are the best examples.  Protect a preparation against the growth of microorganisms. Antimicrobial agents (preservative) are used for such purpose. Others are used in relation to the dosage forms as in suspensions (suspending agents, usually polymers and surface-active agents), establishing emulsified dosage forms (emulsifying agents, usually amphiphilic polymers and surface-active agents), and preparation of liposomes (hydrated phospholipids).  FORMULATION COMPONENTS (SOLVENTS AND SOLUTES) Table 6-3 Dielectric Constants for Various Solvents Dielectric constant Solvent ( ) at 25◦ C Water 78.5 Glycerol 42.5 Propylene glycol 32.0 Polyethylene glycol 400 13.6 Dimethyl sulfoxide 46.7 Dimethylacetamide 37.8 Ethanol 24.3 N-Octanol 10.3 Cottonseed oil 3.0 Solubilizing Agents Solubilizing agents are either co-solvents or amphiphilic compounds classified as either complexing agents or surface-active agents. Co-solvents already have been covered along with examples given earlier in this chapter. A survey of injectable formulations containing co-solvents finds that ethanol and propylene glycol are the most commonly used co-solvents. Both have high solvent power for organic molecules because of a dielectric constant (measure of electric current conductance) in the 24 to 32 range (water is 78, cottonseed oil is 3). Table 6-3 gives dielectric constant () values for several solvents. Dielectric constant is a measure of the electric current conductivity property of solvents. The higher the dielectric constant, the better electric current will travel through the solvent. Thus, water has the highest  while oil has the lowest. Poorly soluble drugs will have greater solubility in solvents whose  is not as high as water. Thus, mixtures of water and one or more water-miscible co-solvents will solubilize slightly polar drugs. The primary problem in using co-solvents is the toxicity of these solvents. In general, small amounts of co-solvents are acceptable, but if the drug dosage is large (i.e., greater than 5 mL), then the usage of co-solvents is limited. Another disadvantage of using co-solvents is the concern for precipitation at the site of injection if the solution is administered too quickly and the blood stream does not have adequate EtOH 10 PEG400 PG 1 Glycerin Fluasterone (mM) 0.1 0.01 0.001 0.0001 0 20 40 60 80 Figure 6-1 Example of co-solvent effect on drug Cosolvent (%) solubility. Source: From Ref. 12.  STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY Table 6-6 Examples of Polysorbates Contained in Commercial Protein Formulations Active ingredient amount Polysorbate Product or concentration Dosage form concentration AranespⓍ R 25–500 µg Liquid 0.05 mg/mL ReoProⓍ R 2 mg/mL Liquid 0.001% HumiraⓍ R 40 mg/mL Liquid 0.8 mg/mL AvastinⓍR 25 mg/mL Liquid 1.6 mg/mL RemicadeⓍ R 10 mg/mL Lyophilized 0.05 mg/mL AralastⓍR 600 mg/mL Lyophilized 0.05 mg/mL ActivaseⓍ R 1 mg/mL Lyophilized 0.09 mg/mL KoateⓍR 1.5 mg/mL Lyophilized 0.025 mg/mL AdvateⓍ R 250–1500 IU Lyophilized 0.17 mg/mL KogenateⓍ R 1000 IU Lyophilized 600 µg NovoSevenⓍ R 0.6 mg/mL Lyophilized 0.1 mg/mL BeneFixⓍ R 250–1000 IU Lyophilized 0.01% TisseelⓍR VH 45 mg Lyophilized 60 mg WinRhoⓍ R SDF 600–5000 IU Lyophilized 0.01% PEG-IntronⓍ R 0.106–0.307 mg/mL Lyophilized 0.106 mg/mL RetavaseⓍ R 1.81 mg/mL Lyophilized 0.52 mg/mL TNKaseⓍ R 5.25 mg/mL Lyophilized 0.43 mg/mL HerceptinⓍ R 22 mg/mL Lyophilized 0.09 mg/mL time to dilute the drug. Also, all co-solvents have hemolytic effects on red blood cells that can be minimized simply by minimizing the amount of co-solvent administered. If the co-solvent approach either is unsuccessful or not preferable, then the next formulation approach to increase drug solubility is the use of surface-active agents (Polysorbates or Tweens and Spans). Surfactants used in parenteral preparations must be non-ionic, to be more safe and less irritant. Surfactants also are used in parenteral suspensions to improve the dispersion properties of the insoluble active drug. Antimicrobial Agents The USP states that antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to preparations contained in multiple-dose containers1. They must be present in adequate concentration at the time of use to prevent the multiplication of microorganisms inadvertently introduced into the preparation while withdrawing a portion of the contents with a hypodermic needle and syringe. Because antimicrobials may have inherent toxicity forthe patient, the USP prescribes maximum volume (30ml) and concentration limits for those that are used commonly in parenteral products (Table 6-7), for example, phenylmercuric nitrate and thimerosal 0.01%, benzethonium chloride and benzalkonium chloride 0.01%, phenol or cresol 0.5%, and chlorobutanol 0.5%. Buffers Buffering agents are used primarily for maintenance of a desired pH for both solubility (if needed) and stability to stabilize a solution against chemical degradation or, affect the preparation solubility. Buffer systems employed should normally have as low a buffering capacity as feasible so as not to disturb significantly the body’s buffering systems when injected. In addition, the buffer type and concentration on the activity of the active ingredient must be evaluated carefully. Buffer components are known to catalyze degradation of drugs. The acid salts most frequently employed as buffers are citrates, acetates, and phosphates. 1 The European Pharmacopeia requires multiple-dose products to be bacteriocidal and fungicidal.  STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY Table 6-7 Examples of Commercial Sterile Dosage Forms Containing Antimicrobial Preservative Agents and Their Concentrations AP agent Concentration Examples (allⓍ R ) Benzyl alcohol 0.9%–3.0% VePesid and Vumon Phenol 0.002%–0.5% Hydeltrasol and Sus-Phrine Meta-Cresol 0.25%–0.3% Humatrope and Genotropin Phenoxyethanol 0.5%–1.0% Poliovax and IpolTM Thimerosal 0.0002%–0.012% Recombivax and Hyperab Chlorobutanol 0.25%–0.5% Aquasol and Oxytocin Methylparaben 0.02%–0.2% Intron A and Gentamicin Propylparaben 0.002%–0.02% Bicillin L-A and Tobramycin Phenylmercuric acetate, 0.01%–0.002% Several topical ophthalmic borate, nitrate medications 0.01%– Benzalkonium/Benzethonium 0.01% Benadryl and many topical chloride ophthalmic medications Source: From Ref. 2. Antioxidants Substances called antioxidants or reducing agents are required frequently to preserve products because of the ease with which many drugs are oxidized. Sodium bisulfite and other sulfurous acid salts are used most frequently. Ascorbic acid and its salts also are good antioxidants. The sodium salt of ethylenediaminetetraacetic acid (EDTA) has been found to enhance the activity of antioxidants in some cases, apparently by chelating metallic ions that would otherwise catalyze the oxidation reaction. Inert Gases Inert gases are frequently used in production of sterile dosage forms. Inert gases are used to displace the air (oxygen) in and above the solution by purging the inert gas, also can be used as a means to control oxidation of a sensitive drug. The most commonly used inert gas is nitrogen. Other inert gases used, although not often primarily because of expense, include argon and helium. The inert gas must be high quality grade and must be sterilized, usually with a 0.22-µm hydrophobic membrane filter. The integrity of the gas filter is tested before and after use by diffusion flow methods. Chelating Agents Chelating agents are used in formulations to aid in inhibiting free radical formation and resultant oxidation of active ingredients caused by trace metal ions such as copper, iron, calcium, man- ganese, and zinc. There are several examples of commercial formulations (NebcinⓍR , Decadron- LAⓍ R , VersedⓍR , CleocinⓍ R , and others) where a chelating is all that is needed, that is, no antioxi- dant in the formulation, to protect the active ingredient against metal- catalyzed oxidation. The most common chelating agent used is disodium ethylenediaminetetraacetic acid (DSEDTA). FORMULATION COMPONENTS (SOLVENTS AND SOLUTES) NaOOCCH2 CH2COONa CH2CH2 N N CH2 Metal Ion CH2 x H2O COO OOC Figure 6-9 Structure of ethylenediaminetetraacetic acid Range of concentrations: 0.004–0.05% (EDTA) disodium salt and how it binds metal ions. Tonicity Agents While it is the goal for every injectable product to be isotonic with physiologic fluids, this is not an essential requirement for small-volume injectables that are administered intravenously. However, products administered by all other routes, especially into the eye or spinal fluid must be isotonic. Injections into the subcutaneous tissue and muscles also should be isotonic to minimize pain and tissue irritation. Tonicity-adjusting agents most commonly used are electrolytes (sodium chloride most common), glycerin, and mono- or disaccharides. Cryoprotectants and Lyoprotectants These substances serve to protect biopharmaceuticals from adverse effects due to freezing and/or drying of the product during freeze-dry processing. Sugars (non-reducing) such as sucrose or trehalose, amino acids such as glycine or lysine, polymers such as liquid polyethylene glycol or dextran, and polyols such as mannitol or sorbitol all are possible cryo- or lyoprotectants. Several theories exist to explain why these additives work to protect proteins against freezing and/or drying effects. Excipients that are preferentially excluded from the surface of the protein are the best cryoprotectants, and excipients that remain amorphous duri ng and after freeze-drying serve best as lyoprotectants. These concepts of additive stabilization of biophar- maceuticals during freezing, drying, and/or in the dry state are covered in chapter 10. Competitive Binders These additives are used if the active ingredient is known to bind excessively to container and manufacturing equipment surfaces. Such additives compete with the active ingredient for the surface-binding sites and keep the active ingredient from losing potency or activity in the dosage form. Historically, the best or most commonly used competitive binder has been human serum albumin (HSA) at concentrations ranging from 0.1% to 1.0%. Other Additives Other purposes for solute additives in sterile product formulations include bulking agents for freeze-dried products, suspending agents and wetting agents for suspensions, emulsifying agents for emulsions, viscosity-inducing agents for topical ophthalmic products, and the specialized polymers used to formulate advanced sustained-, prolonged-, extended-, delayed-, or controlled-release dosage forms (microspheres, liposomes, gels, and other specialized injectable delivery systems). While most of the dosage forms and formulation additives are covered in other chapters, a summary of the examples of additives used in specialized sterile dosage forms is given in Table 6-8. 68 STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY Table 6-8 Examples of Additives Used in Specialized Sterile Dosage Forms Dosage form Purpose of additive Primary examples Freeze-dried products Bulking agents Mannitol Glycine Sodium phosphate Suspensions Wetting agents Surfactants (e.g., Polysorbate 80) Lecithin Sorbitol trioleate Suspending agents Sodium methylcellulose Sodium carboxymethylcellulose Polyethylene glycol Propylene glycol Polyvinylpyrrolidone Sodium alginate Emulsions Emulsifying agents Egg yolk phospholipid Lecithin Surfactants Topical ophthalmic solutions Viscosity-inducing agents Hydroxypropyl methylcellulose Polyvinyl alcohol Liposomes Incorporate active ingredient for targeting See Table 3-3 or other distribution mechanism Extended-release products Affect release of drug from injected Polylactic-polyglycolic polymers formulation Polyanhydrides Poly(orthoesters) Poly(2-hydroxyethyl methacrylate) Hyaluronic acid Polyethylene glycol (pegylation) STERILE DRUG PRODUCTS: FORMULATION, PACKAGING, MANUFACTURING, AND QUALITY