Parenteral Formulations

Ophthalmic Preparations

Products to be instilled into the eye, while not parenteral by definition have many similar, and often identical, characteristics. The formulation of stable, therapeutically-active ophthalmic preparations requires high purity of ingredients as well as freedom from chemical, physical (particles), and microbial contaminants. These preparations usually require buffers to stabilize the pH of the product, additives to render it isotonic or nearly so, and stabilizers such as antioxidants when appropriate for the particular ingredients. Those ophthalmic used in larger quantities, such as eye irritants, or in the case of devices such as contact lenses, are usually relatively uncomplicated solutions similar to large-volume parenterals.

One feature not as critical for ophthalmics is freedom from pyrogens since pyrogens are not absorbed systemically from the eye; however, in so far as pyrogens are indicative of a microbiologically clean process, they should not be present.

Freeze-dried Products

A solution intended to be freeze-dried must be aqueous, for the drying process involves the removal of water by sublimation. Since the solution is in existence for only a brief period during processing, stability problems related to the aqueous system are practically non-existent. However, the formulation must reflect the characteristics to be imparted to the solid residue (cake) after drying, and those required of the solution after reconstitution at the time of use. Often, the drug alone does not give sufficient solid residue or the characteristics appropriate for the product; therefore, substances often must be added to provide the characteristics desired.

Among the characteristics required of a good cake are

• Uniform color and texture.
• A supporting matrix of solids is sufficient to maintain essentially the original volume after drying.
• Sufficient strength to prevent crumbling during storage.

In addition, the nature and amount of solids in the solution largely determine

• The eutectic temperature of the frozen solution, the subzero temperature at which the frozen material will melt, which determines the temperature below which the product must be held during freeze-drying.
• The rate of thermal and vapor transfer through the product during the process of drying.
• The rate of solution of the product during reconstitution. The percentage of solids in the frozen plug should be between approximately 2 and 25%. Among the best salts for providing uniformity.

Long-acting Formulations

The long-acting parenteral formula is ideally designed to provide slow and sustained release of a drug over a prolonged period of time, essentially to simulate and replace the more hazardous, continuous i.v. infusion of a drug.

Types of Depot Formulation

1. Dissolution controlled
2. Binding of drug molecules to adsorbents
3. Encapsulation type
4. Esterification type

Dissolution-controlled: The rate of drug absorption is controlled by the slow dissolution of drug particles, with subsequent release to tissue fluid surrounding the bolus of product in the tissue. The formation of drug salts with very low aqueous solubility is one of the most common approaches to this type of formulation. Further, the suspension of the drug particles in the vegetable oils, especially if gelled with substances such as aluminum monostearate produces prolonged absorption rates.

Binding of drug molecules to adsorbents: Only the free portion, in equilibrium with that which is bound can be absorbed. As the drug is absorbed, a shift in the equilibrium is established, and the drug is released from the bound state to the Free State. Ex: Binding of vaccine to aluminum hydroxide gel to provide sustained release.

Encapsulation type: In this type, biodegradable or bioabsorbable macromolecules are used which serve as a diffusion matrix for the drug. Here the release is controlled by the rate of permeation out of the barrier and the rate of biodegradation of the barrier macromolecules.

Esterification type: In which the rate of absorption is controlled by the partitioning of the drug esters from the reservoir to the tissue fluid and by the rate at which the drug ester regenerates the active drug molecules.

Biphasic (Suspension)

The solid content of the parenteral suspension usually ranges between 0.5 and 5% but may go as high as 30% in some antibiotic preparations. The number of solids and the nature of the vehicle determines the viscosity of the product, and sometimes the property of thixotropy is also utilized particularly with oleaginous suspensions, to provide the sedimentation stability of the gelled preparation during storage and the syringe ability of fluid at the time of administration. Probably the most important requirement for parenteral suspension is small and uniform particle size. These factors give slow, uniform rates of sedimentation, predictable rates of dissolution, drug release and also reduce the tendency for larger crystal growth during storage.

The stabilization of the suspension for the period between the manufacturer and use presents a number of problems. As indicated, solids gradually settle and may cake, causing difficulty in redispersion prior to use. Surface active agents may aid in the preparation and stabilization of the suspension by reducing the interfacial tension between the particles and the vehicle.

Similarly, the addition of hydrocolloids such as sodium carboxymethylcellulose enhances the effect of surfactant and causes loss of surface charge of the dispersed particles, water repellency, and the tendency to agglomerate.

Emulsions

The principal problem in the formulation of parenteral emulsions is the accomplishment and maintenance of the uniform oil droplets of 1 to 5 µm in size as the internal phase. In the case of emulsion separation of the phase does not occur compared to the suspension because the difference in density between the oil and water is relatively small. The dispersed phase should have droplet sizes of less than 1µm. The emulsion must be stable to autoclaving. However elevated temperature produces coalescence of the dispersed phase and excessive shaking causes have been found to aid in stabilizing but are adversely affected by the elevated temperatures.

Difficulty:

• Preparation is troublesome.
• It’s more complicated because of the rigid requirement of the particle size control to prevent embolism in blood vessels
• Also the limited choice of the emulsifiers and stabilizers of low toxicity, and by the preservation of the oil phase against the development of rancidity.

Formulation Development

The main objective is the elicitation of a therapeutic effect in the patient. The parenteral formulations of sterile products involve the combination of one or more ingredients with the medicinal agents to enhance the convenience, acceptability, or effectiveness of the product.

Therapeutic Agent:

• It is a chemical compound subject to the physical and chemical reaction characteristics of the class of the compound to which it belongs.
• Therefore careful evaluation must be made for every combination to ascertain whether adverse interaction occurs.
• Information concerning basic properties must be obtained including molecular weight, solubility, purity, colligative properties, and chemical properties.

Vehicle or Solvent System

Aqueous System:

• The most commonly employed vehicle is water since it is the vehicle for all-natural body fluids.
• The most tests for the quality of water are total solids content, gravimetric evaluation of the dissociated and undissociated organic and inorganic substances present in water.
• Electrolytic measurement of conductivity of water is the most frequently used method. Measurement can be achieved by immersing the electrode in water and measuring the specific conductance.
• Additional tests: Quality of water for injection with permitted limits is described in the USP monographs. The 10 ppm (parts per million) total solids officially permitted for Water for injection may be much too high when used as a vehicle for many products. Water shall retain a minimal amount of organic compounds. Such compounds are undesirable for two main reasons: they may be toxic, and they may serve as sources of nutrition for microorganisms.
• Water for Injection normally should not have a conductivity of more than 1 micromho (1 megohm, approximately 0.1 ppm NaCl) and total organic carbon (TOC), not more than 500 ppb.

Non-aqueous and Mixed Solvents:

• In the formulation of sterile pharmaceutical products, it is sometimes necessary to eliminate water entirely or in part from the vehicle, because of solubility factors or hydrolytic reactions.
• A non-aqueous solvent must be selected with great care for it must not be irritating, toxic, or sensitizing, and it must not exert an adverse effect on the ingredients of the formulation.
• The screening of such solvent must therefore include an evaluation of its physical properties such as density, viscosity, miscibility, and polarity, as well as its stability, solvent activity, and toxicity.
• Solvents that are miscible with water and that are usually used in combination include dioxolanes, dimethylacetamide, N-(6-hydroxyediy1)-lactamide, butylene glycol, polyethylene glycol 400 and 600, propylene glycol, glycerin, and ethyl alcohol.
• Water-immiscible solvents like fixed oils, edible oleate, isopropyl myristate, and benzyl benzoate. The most frequently used non-aqueous solvents are polyethylene glycol, propylene glycol, and fixed oils.

Solvent Selection:

• If aqueous, the solution is physiologically compatible with body tissues and the biologic response elicited should be reasonably predictable.
• The high dielectric constant of water makes it possible to dissolve ionizable electrolytes, and its hydrogen bonding potential brings about the solution of such organic substances as alcohols, aldehydes, ketones, and amines.
• Since therapeutically active compounds given by injection range in property from highly polar to non-polar, solvents having complementary properties must be employed if a solution is to be achieved.
• Solvents to be injected must be of low toxicity to the body tissue.
• The use of mixed solvents often reduces degradative reactions. Ex: Barbituric acid derivatives hydrolyze readily in water, particularly at a low pH.

Solutes:

• The physical and chemical purity of solutes used for sterile preparations must also be exceptional. Obviously, the contaminants entering a product with a solute have the same effect as if they entered via the vehicle. Even small traces of contaminants may be detrimental to products, necessitating purification of the solute. For a few substances (for example, ascorbic acid and calcium gluconate), special parenteral grades are commercially available.
• Solutes should be free from microbial and pyrogenic contamination. This entails not only the proper quality of the chemical as procured but also storage conditions designed to prevent contamination, particularly after a container has been opened.

• Substances added to a product to enhance its stability are essential for almost every product. Such substances include solubilizers, antioxidants, chelating agents, buffers, tonicity contributors, antibacterial agents, antifungal agents, hydrolysis inhibitors, antifoaming agents, and numerous other substances for specialized purposes.
• These agents must be prevented from adversely affecting the product. Added substances must be non-toxic in the quantity administered to the patient. They should not interfere with the therapeutic efficacy or with the assay of the active therapeutic compound.
• They must also be present and active when needed throughout the useful life of the product. Therefore, these agents must be selected with great care and must be evaluated as to their effect upon the entire formulation.

Antibacterial Agent:

Antibacterial agents in bacteriostatic concentration must be included in the formulation of products packaged in multiple-dose vials, and are often included in formulations to be sterilized by marginal processes or made by aseptic manipulation.

Antioxidants:

In many formulations antioxidants are added to protect a therapeutic agent susceptible to oxidation, particularly under the accelerated conditions of thermal sterilization, may function in at least two ways:

1. By being preferentially oxidized (reducing agents), and thereby gradually used up.
2. By blocking an oxidative chain reaction in which they are not usually consumed.

In addition, certain compounds have been found to act as synergists, increasing the effectiveness of antioxidants, particularly those blocking oxidative reactions. The fourth group of compounds is useful in this connection in that they are complex with catalysts that otherwise would accelerate the oxidative reaction.

Buffers:

• These are added to maintain the required pH for many products, as the change in pH may cause significant alterations in the rate of degradative reactions.
• Changes in pH may occur during storage as a result of the dissolution of glass constituents in the product, release of constituents from rubber closures or plastic components in contact with the product, dissolution of gases and vapors from the airspace in the container, and diffusion through the rubber or plastic component, or reactions within the product.
• Buffers must have the capacity to maintain the pH of the product against these influences, but not enough to prevent the body fluids from overwhelming the buffer following administration.
• Acetates, citrates, and phosphates are the principal buffer systems used. Buffer systems must be selected with consideration of their effective range, concentration, and chemical effect on the total product.

Tonicity Contributors:

• Compounds contributing to the isotonicity of a product reduce the pain of injection in areas with nerve endings.
• Various agents used to adjust tonicity are such as sodium chloride or other sodium salts and non-electrolytes such as glycerin and lactose are most commonly used for this purpose.
• Tonicity adjusters are usually the last ingredients added to the formulation and the osmolality of the formulation is measured. Although the freezing point depression of the solution is most frequently used to determine whether a solution is isotonic, isotonicity actually depends on the permeability of a living semipermeable membrane that separates the solution from a biologic cell system.
• Most frequently for sterile pharmaceutical preparations, the membrane concerned is the one enclosing the red blood cells.
• Preparation cannot be considered to be isotonic until it has been tested in a biological system. This has been described by the hemolytic method. If the formulation is still isotonic (< 280 mOsm/ kg as measured by an osmometer), tonicity adjusters are added until the formulation is isotonic. If the formulation is hypertonic, the degree of hypotonicity and the intended route of drug administration need to be considered.

Chelating Agents:

• These may be added to bind, in non-ionizable form, trace amounts of heavy metals, which if free would catalyze degradative changes.
• The most commonly used chelating agents are: trisodium/calcium disodium salt of ethylene diamine tetra-acetic acid in the range of 0.05% (w/v) E.g. Stabilization of thimerosal in poliomyelitis vaccine.

Inert Gases:

• These have been used to displace oxygen from a solution and reduce the possibility of oxidative changes in the formulation. E.g. Sodium bicarbonate injection decomposes, particularly during autoclaving to produce sodium carbonate, carbon dioxide, and water.
• The saturation of the solution with carbon dioxide inhibits this reaction and stabilizes the solution.

Protein Stabilizers:

• A number of ingredients have been shown to stabilize proteins both in the dry and solution state.
• Serum albumin competes with therapeutic proteins for binding sites in glass and other surfaces and minimizes the loss of the protein caused by surface binding.
• A number of different types of substances are used as cryoprotectants and cryoprotectants to minimize protein denaturation during freeze-drying.
• Primary examples include polyhydric alcohols (sorbitol, glycerol, polyethylene glycol); amino acids (glycine, lysine, glutamine); non-reducing sugars (trehalose, sucrose); and polymers such as dextran, polyvinylpyrrolidone, and methyl-cellulose. Surface active agents, such as Poloxamer 188 (Pluronic 68), polysorbate 80, and polysorbate 20 are widely used to minimize protein aggregation at air/water and water / solid interfaces.
• Antioxidants, buffers, and chelating agents are also used to stabilize proteins in solution when necessary.
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