Dosage forms

Variations in Dosage Form Insulin solution. Dissolved insulin is dispensed as a clear neutral solution known as regular (R) insulin or crystalline zinc insulin. In emergencies, such as hyperglycemic coma, 

Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

Insulin suspensions. When it is injected as a suspension of insulin-containing particles, dissolution and release of the hormone in subcutaneous tissue is retarded (extended-action insulins). Suitable particles can be obtained by precipitation of apolar, poorly water-soluble complexes consisting of anionic insulin and cationic partners, e.g., the polycationic protein protamine. In the presence of zinc ions, insulin crystallizes crystal size determines the rate of dissolution. Intermediate-acting insulin preparations (NPH or isophane Lente) act for 18-26 hours, slow-acting preparations (protamine zinc, ultralente) for up to 36 hours. 

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Fine chemicals are produced by a wide spectmm of manufacturers, largely because the distinction between different kinds of chemicals is not sharp. There are specialty producers of fine chemicals. Many companies that manufacture dmgs also manufacture the chemical substances that are used in preparing the dosage forms. A number of companies manufacture dmg chemicals and food chemicals. Some fine chemicals are made by manufacturers of heavy chemicals, and either may be simply a segment of their regular production, or some of that production which has been subjected to additional purification steps. Many fine chemicals are imported into the United States from countries such as Japan, Germany, and the Netherlands. 

Standards for dmg chemicals are pubUshed ia USP—NE. Dmg substances are chemicals that have therapeutic or diagnostic uses, whereas pharmaceutical iagredients provide preservative action, fiavoiing, or hilfillment of a function ia the formulation of dosage-form dmgs. Examples of dmg substances are acetaminophen [103-90-2] ampicillin [69-53-4] aspirin [50-78-2] powdered ipecac, riboflavin [83-88-5] staimous fluoride [7783-47-3] and thyroid. Examples of pharmaceutical iagredients are ethylparaben [120-47-8] lactose [63-42-3] magnesium stearate [557-04-0] sodium hydroxide [1310-73-2] starch [9005-25-8] and vanillin [121-33-5],... 

The early USPC was dominated by physicians who selected the best dmgs. This prevented iaclusion ia the USP of a large number of substances that were widely used, particularly elixirs, a popular dosage form ia the late nineteenth ceatury. To fill this gap, ia 1888 the American Pharmaceutical Association pubUshed the first NE, which provided standards for dmgs ia wide use but aot iacluded ia the USP. A history of the Natioaal Eormulary is also iacluded at the froat of the NF sectioa ia USP XXII—NFXUII (5). 

PhRMA is a trade association of over 100 research-based pharmaceutical companies. For membership a company must manufacture and market finished dosage-form products under its own brand names and must conduct a significant amount of research and development in the United States. 

Concepts and Processes. Contemporary dosage forms are dmg dehvery systems, designed and manufactured to achieve safe and effective therapeutic responses each time the forms are used as part of an appropriate regimen. Thus, the intent of the prescriber is accompHshed when the product is used compliantly by the patient (12—14). Each dmg product involves several interrelated concepts that must be considered in its design and manufacture (15). Examples include the following ... 

The various preparation processes and technologies used in dmg product manufacture also can effect product safety, stabihty, and performance, eg, compression during tablet manufacture. The principal processes used in dosage form manufacture are as foUows (15). 

Biological characterization includes toxicological studies, dose relationships, routes of adininistration, identification of side effects, and absorption, distribution, metaboHsm, and excretion patterns. If the results are stiU acceptable, product formulation and dosage form are developed. The product should be pleasing to the patient and thus may contain flavoring and colorants. 

Two similar dosage forms, eg, tablets, that contain the same amount of the same dmg entity and meet USP/NF and current good manufacturing practices (FDA) are referred to as pharmaceutical equivalents (PE). When, upon adiriinistration, such tablets achieve similar profiles of AUC, and... 

In cases of all but intravenous adininistration, dosage forms must make the active moiety available for absorption, ie, for dmg release. This influences the bioavailabiUty and the dmg s pharmacokinetic profile. Ideally the dmg is made available to the blood for distribution and elimination at a rate equal to those processes. Through technological developments dmg product design can achieve release, absorption, and elimination rates resulting in durations of activity of 8—12 hours, ie, prolonged action/controlled release dmg products (21,22). Such products improve the compliance rate of dmg usage by patients. 

Compressed Tablets. This popular type of dosage form offers convenience, stabiUty, accuracy and precision, and good bioavadabihty of active ingredients. After the best formulation has been estabflshed, compressed tablets can be manufactured at high rates of speed on advanced equipment. Tablets can be made to achieve rapid dmg release or to produce delayed, repeat, or prolonged therapeutic action (Controlled release technology, pharmaceutical). ... 

Since the development of the Spansule brand (Smith Kline Beech am) of coated beads and granules in the late 1960s, various dmg product technologies have been developed and patented to achieve extended durations of therapeutic effects. Each of these does so by various mechanisms of control of dmg release from adrninistered dosage forms. Each method has its advantages and disadvantages, a discussion of which is available in the pharmaceutical hterature (see Drug delivery systems) (21). 

Delayed action soHd products are designed like conventional dosage forms to release all their dmg contents at one time, but only after a delayed period. Thus, the duration of action and the blood concentration—time curve is like that of a conventional product. However, the onset time is purposely designed to be long. 

Liquid Dosage Forms. Simple aqueous solutions, symps, elixirs, and tinctures are prepared by dissolution of solutes in the appropriate solvent systems. Adjunct formulation ingredients include certified dyes, flavors, sweeteners, and antimicrobial preservatives. These solutions are filtered under pressure, often using selected filtering aid materials. The products are stored in large tanks, ready for filling into containers. QuaUty control analysis is then performed. 

Dosage forms of naturally occurring materials having therapeutic activity are prepared by extractive processes, especially percolation and maceration. Examples of such dosage forms have included certain tinctures, symps, fluid extracts, and powdered extracts. 

The USP recognizes three forms of water for parenteral dosage forms. Water for injection is prepared by reverse osmosis or distillation, which... 

Ophthalmic Dosage Forms. Ophthalmic preparations can be solutions, eg, eye drops, eyewashes, ointments, or aqueous suspensions (30). They must be sterile and any suspended dmg particles must be of a very fine particle size. Solutions must be particle free and isotonic with tears. Thus, the osmotic pressure must equal that of normal saline (0.9% sodium chloride) solution. Hypotonic solutions are adjusted to be isotonic by addition of calculated amounts of tonicity adjusters, eg, sodium chloride, boric acid, or sodium nitrate. 

Aerosols. Pressurized containers to deHver aerosolized dmg products through appropriate systems of valves and actuators have been available since the 1950s (see Aerosols). Such dosage forms are used as external appHcations of lotions and creams, for oral inhalation, or for treatment of the vaginal cavity, eg, contraceptive foams. Aerosols contain two- or three-phase systems, wherein a volatile Hquid or admixture of Hquids is sealed in a... 

Good Manufacturing Practice. The GMPs were issued by the U.S. FDA in 1978 to provide minimum quahty standards in the production of pharmaceuticals (qv) for the finished dosage form as well as their ingredients. The standard has been updated periodically. 

Uses. Aspirin has analgesic, antiinflammatory, and antipyretic activity. It is used for the reHef of less severe types of pain, such as headache, neuritis, acute and chronic rheumatoid arthritis, and toothache. Aspirin can be purchased in a variety of OTC and prescription dosage forms made and formulated by many companies. Tablets, ie, buffered, plain, or enteric-coated, are the most familiar in the United States, but other forms such as powder and effervescent formulations are of considerable importance in other parts of the world. 

S. Turco and R. E. King, Sterile Dosage Forms, Their Preparation and Clinical Application, Lea and Eebiager, Philadelphia, Pa., 1974. 

Pharmaceuticals. Examples of trace and ultratrace analyses of various dmgs and pharmaceuticals have been provided throughout. The purity of the active ingredient, its content and availabiUty in dosage form, therapeutic blood levels, deflvery to target areas, elimination (urine, feces, and metabohtes), and toxicity are always of importance. 

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