8 Drug Administration Dosage Forms for Oral, Ocular, and be very precise (Standardized medici- nal teaspoons and tablespoons are A medicinal agent becomes a medica- ion only after formulation suitable for designed for application to the mucosa herapeutic use (ie. in an appropriate surfaces of the eye(conjunctival sac) osage form). The dosage form takes and nasal cavity, respectively. In orde nto account the intended mode of use to prolong contact time, nasal drops are and also ensures ease of handling(e. g, formulated as solutions of increased tients and physicians. Pharmaceutical Solid dosage forms include tab chnology is concerned with the design lets, coated tablets, and capsules(b) f suitable product formulations and Tablets have a disk-like shape, p uality control. duced by mechanical compression of Liquid preparations (A)may take active substance, filler(e. g, lactose, cal ol or mixture consisting of small wa- terial (excipients ). The filler provides er-insoluble solid drug particles dis- bulk enough to make the tablet easy to or a drug solution in another fluid, e g, many drugs lies in the range of a few oil orage will cause milligrams or less. In order to conv edimentation of suspensions and sep- the idea of a 10-mg weight, two square aration of emulsions, solutions are g marked below, the paper mass erally preferred. In the case of poorly each weighing 10 mg Disintegration watersoluble substances, solution is of- the tablet can be hastened by the use ten accomplished by adding ethanol (or dried starch, which swells on contact other solvents); thus, there are both with water, or of NaHCO. which releas- queous and alcoholic solutions. These es Co2 gas on contact with gastric aci n specially designed drop bottles, ena- regard to tablet production, shelf life. bling single doses to be measured t palatability, and identifiability(color) ctly in terms of a defined number Effervescent tablets(compresse area of the drip opening at the bottle a solid dosage w ders)do not represent drops, the size of which depends on the effervescent po nouth and on the viscosity and surface dissolved in water immediately prior to tension of the solution. The advantage ingestion and are, thus, actually, liquid of a drop solution is that the dose, that preparations. is, the number of drops, can be prec ly adjusted to the patients need. Its dis- advantage lies in the difficulty me patients, disabled by disease or age, will experience in measuring a pre scribed number of drops. When the drugs are dissolved in a mg or mixtures the single dose is mea ured with a measuring spoon. Dosing ay also be done with the aid of a tablespoon or teaspoon(approx 15 and 10 5 ml, respectively ) However, due to the wide variation in the size of commer g n cially available spoons, dosing will not LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Dosage Forms for Oral, Ocular, and Nasal Applications A medicinal agent becomes a medication only after formulation suitable for therapeutic use (i.e., in an appropriate dosage form). The dosage form takes into account the intended mode of use and also ensures ease of handling (e.g., stability, precision of dosing) by patients and physicians. Pharmaceutical technology is concerned with the design of suitable product formulations and quality control. Liquid preparations (A) may take the form of solutions, suspensions (a sol or mixture consisting of small water-insoluble solid drug particles dispersed in water), or emulsions (dispersion of minute droplets of a liquid agent or a drug solution in another fluid, e.g., oil in water). Since storage will cause sedimentation of suspensions and separation of emulsions, solutions are generally preferred. In the case of poorly watersoluble substances, solution is often accomplished by adding ethanol (or other solvents); thus, there are both aqueous and alcoholic solutions. These solutions are made available to patients in specially designed drop bottles, enabling single doses to be measured exactly in terms of a defined number of drops, the size of which depends on the area of the drip opening at the bottle mouth and on the viscosity and surface tension of the solution. The advantage of a drop solution is that the dose, that is, the number of drops, can be precisely adjusted to the patient‘s need. Its disadvantage lies in the difficulty that some patients, disabled by disease or age, will experience in measuring a prescribed number of drops. When the drugs are dissolved in a larger volume — as in the case of syrups or mixtures — the single dose is measured with a measuring spoon. Dosing may also be done with the aid of a tablespoon or teaspoon (approx. 15 and 5 ml, respectively). However, due to the wide variation in the size of commercially available spoons, dosing will not be very precise. (Standardized medicinal teaspoons and tablespoons are available.) Eye drops and nose drops (A) are designed for application to the mucosal surfaces of the eye (conjunctival sac) and nasal cavity, respectively. In order to prolong contact time, nasal drops are formulated as solutions of increased viscosity. Solid dosage forms include tablets, coated tablets, and capsules (B). Tablets have a disk-like shape, produced by mechanical compression of active substance, filler (e.g., lactose, calcium sulfate), binder, and auxiliary material (excipients). The filler provides bulk enough to make the tablet easy to handle and swallow. It is important to consider that the individual dose of many drugs lies in the range of a few milligrams or less. In order to convey the idea of a 10-mg weight, two squares are marked below, the paper mass of each weighing 10 mg. Disintegration of the tablet can be hastened by the use of dried starch, which swells on contact with water, or of NaHCO3, which releases CO2 gas on contact with gastric acid. Auxiliary materials are important with regard to tablet production, shelf life, palatability, and identifiability (color). Effervescent tablets (compressed effervescent powders) do not represent a solid dosage form, because they are dissolved in water immediately prior to ingestion and are, thus, actually, liquid preparations. 8 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Administration 9 in drops Alcoholic O drops= 1g Solution A Liquid preparations MAng and n 500mg Coated tablet B Solid preparations for oral application C. Dosage forms controlling rate of drug dissolution LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 9 C. Dosage forms controlling rate of drug dissolution B. Solid preparations for oral application A. Liquid preparations Drug Filler Disintegrating agent Other excipients Mixing and forming by compression ~0.5 – 500 mg 30 – 250 mg 20 – 200 mg 30 – 15 mg min 100 – 1000 mg max possible tablet size Effervescent tablet Tablet Coated tablet Capsule Eye drops Nose drops Solution Mixture Alcoholic solution 40 drops = 1g Aqueous solution 20 drops = 1g Dosage: in drops Dosage: in spoon Sterile isotonic pH-neutral Viscous solution Drug release Capsule Coated tablet Capsule with coated drug pellets Matrix tablet Time 5 - 50 ml 5 - 50 ml 100 - 500 ml Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
10 Drug Administration The coated tablet contains a drug with- sit time, drug release can be timed to oc- a core that is covered by a shell, e. g, a cur in the colon. ax coating, that serves to: (1)protect mask a disagreeable taste or odor; (3) drug is presented in the form of a granu ermit color coding. waxy film of graded thickness Depend- apsules usually consist of an ob- ing on film thickness, gradual dissolu- long casing -generally made of gelatin tion occurs during enteral transit, re that contains the drug in powder or leasing drug at variable rates for absorp- granulated form( See p 9. C). ion. The principle illustrated for a cap In the case of the matrix-type tab- sule can also be applied to tablets. In this let, the drug is embedded in an inert case, either drug pellets coated with ms of various thicknesses are com- diffusion upon being moistened In con- pressed into a tablet or the drug is incor trast to solutions, which permit direct porated into a matrix-typ blets to break up and capsules to open (disintegration) before the drug can be dissolved (dissolution) and pass lining(absorption). Because dis This kind of retarded drug releas tion of the tablet and dissolution of the is employed when a rapid rise in bloo drug take time, absorption will occur ainly in the intestine (A, track 2). In sorption is being slowed in order to pro the case of a solution, absorption starts long the action of drugs that have a n the stomach(A, track 3). short sojourn in the body For acid-labile drugs, a coating of a cellulose acetate polymer is ill take place in the duodenum at nor- lal speed (A, track 1)and drug libera- tion is not retard The liberation of drug. hence the site and time-course of absorption, are ect to modification by he case of the matrix tablet, the drug is corporated into a lattice from which it can be slowly leached out by gastroin- testinal fluids. As the matrix tablet undergoes enteral transit, drug libera- tion and absorption proceed en route(A, track 4). In the case of coated tablets, coat thickness can d absorption of drug occur A, track 5)bowel. Thus, by matching dissolution time with small-bowel tran- LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
The coated tablet contains a drug within a core that is covered by a shell, e.g., a wax coating, that serves to: (1) protect perishable drugs from decomposing; (2) mask a disagreeable taste or odor; (3) facilitate passage on swallowing; or (4) permit color coding. Capsules usually consist of an oblong casing — generally made of gelatin — that contains the drug in powder or granulated form (See. p. 9, C). In the case of the matrix-type tablet, the drug is embedded in an inert meshwork from which it is released by diffusion upon being moistened. In contrast to solutions, which permit direct absorption of drug (A, track 3), the use of solid dosage forms initially requires tablets to break up and capsules to open (disintegration) before the drug can be dissolved (dissolution) and pass through the gastrointestinal mucosal lining (absorption). Because disintegration of the tablet and dissolution of the drug take time, absorption will occur mainly in the intestine (A, track 2). In the case of a solution, absorption starts in the stomach (A, track 3). For acid-labile drugs, a coating of wax or of a cellulose acetate polymer is used to prevent disintegration of solid dosage forms in the stomach. Accordingly, disintegration and dissolution will take place in the duodenum at normal speed (A, track 1) and drug liberation per se is not retarded. The liberation of drug, hence the site and time-course of absorption, are subject to modification by appropriate production methods for matrix-type tablets, coated tablets, and capsules. In the case of the matrix tablet, the drug is incorporated into a lattice from which it can be slowly leached out by gastrointestinal fluids. As the matrix tablet undergoes enteral transit, drug liberation and absorption proceed en route (A, track 4). In the case of coated tablets, coat thickness can be designed such that release and absorption of drug occur either in the proximal (A, track 1) or distal (A, track 5) bowel. Thus, by matching dissolution time with small-bowel transit time, drug release can be timed to occur in the colon. Drug liberation and, hence, absorption can also be spread out when the drug is presented in the form of a granulate consisting of pellets coated with a waxy film of graded thickness. Depending on film thickness, gradual dissolution occurs during enteral transit, releasing drug at variable rates for absorption. The principle illustrated for a capsule can also be applied to tablets. In this case, either drug pellets coated with films of various thicknesses are compressed into a tablet or the drug is incorporated into a matrix-type tablet. Contrary to timed-release capsules (Spansules®), slow-release tablets have the advantage of being dividable ad libitum; thus, fractions of the dose contained within the entire tablet may be administered. This kind of retarded drug release is employed when a rapid rise in blood level of drug is undesirable, or when absorption is being slowed in order to prolong the action of drugs that have a short sojourn in the body. 10 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Administration 11 Administration in form of Matrix A. Oral administration: drug release and absorption LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Administration 11 Administration in form of Entericcoated tablet Tablet, capsule Drops, mixture, effervescent solution Matrix tablet Coated tablet with delayed release A. Oral administration: drug release and absorption 12345 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
12 Drug Administration orms for Parenteral (1) he rectum or vagina. The resulting oily ry(2) Rectal or Vaginal (3). spreads over the mucosa and en ables the drug to pass into the mucosa. orally(ie, by swallowing), but mastered (p 16)are applied to the skin surface. In Drugs need not always be admini but are used for skin protection or care. al absorption is also bypassed when cal action on the outer skin or.mpl. ly refers to an injection, although enter- However, drugs may be added if a topi- drugs are inhaled or applied to the skin. rarely, a systemic effect is intended. For intravenous, intramuscular Transderm systems are pasted to the epiderm nrough the skin. They offer the advan articular injection. An injectable solu- tage that a drug depot is attached non- tion must be free of infectious agents g to be administered in a manne ould have the same osmotic pre ar to an infusion, Drug ssUe as body fluids in order to avoid his type of delivery mu le of penetrating the cu Solutions for injection are preserved in rier; (2)be effective in very small dose airtight glass or plastic sealed contain- (restricted capacity of reservoir ): and rs From ampules for multiple or sin- (3)possess a wide therapeutic margin le use, the solution is aspirated via a(dosage not adjustable). eedle into a syringe. The cartridge pule is fitted into a special injector that nables its contents to be emptied via administered over an extended od of time. solutions for infusion meet the same standards as solu- for injection. the respiratory tract [p. 14)). An aerosol 15a n a gas, such as air. An aerosol results when a drug solution or micronized riven through the nozzle of a pressu mucosal application of drug via the ectal or vaginal route is achieved means of suppositories and vaginal tablets, respectively. On rectal applica- tion, absorption into the systemic circu- drug is incorporated into a fat that solid- fies at room temperature, but melts in LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Dosage Forms for Parenteral (1), Pulmonary (2), Rectal or Vaginal (3), and Cutaneous Application Drugs need not always be administered orally (i.e., by swallowing), but may also be given parenterally. This route usually refers to an injection, although enteral absorption is also bypassed when drugs are inhaled or applied to the skin. For intravenous, intramuscular, or subcutaneous injections, drugs are often given as solutions and, less frequently, in crystalline suspension for intramuscular, subcutaneous, or intraarticular injection. An injectable solution must be free of infectious agents, pyrogens, or suspended matter. It should have the same osmotic pressure and pH as body fluids in order to avoid tissue damage at the site of injection. Solutions for injection are preserved in airtight glass or plastic sealed containers. From ampules for multiple or single use, the solution is aspirated via a needle into a syringe. The cartridge ampule is fitted into a special injector that enables its contents to be emptied via a needle. An infusion refers to a solution being administered over an extended period of time. Solutions for infusion must meet the same standards as solutions for injection. Drugs can be sprayed in aerosol form onto mucosal surfaces of body cavities accessible from the outside (e.g., the respiratory tract [p. 14]). An aerosol is a dispersion of liquid or solid particles in a gas, such as air. An aerosol results when a drug solution or micronized powder is reduced to a spray on being driven through the nozzle of a pressurized container. Mucosal application of drug via the rectal or vaginal route is achieved by means of suppositories and vaginal tablets, respectively. On rectal application, absorption into the systemic circulation may be intended. With vaginal tablets, the effect is generally confined to the site of application. Usually the drug is incorporated into a fat that solidifies at room temperature, but melts in the rectum or vagina. The resulting oily film spreads over the mucosa and enables the drug to pass into the mucosa. Powders, ointments, and pastes (p. 16) are applied to the skin surface. In many cases, these do not contain drugs but are used for skin protection or care. However, drugs may be added if a topical action on the outer skin or, more rarely, a systemic effect is intended. Transdermal drug delivery systems are pasted to the epidermis. They contain a reservoir from which drugs may diffuse and be absorbed through the skin. They offer the advantage that a drug depot is attached noninvasively to the body, enabling the drug to be administered in a manner similar to an infusion. Drugs amenable to this type of delivery must: (1) be capable of penetrating the cutaneous barrier; (2) be effective in very small doses (restricted capacity of reservoir); and (3) possess a wide therapeutic margin (dosage not adjustable). 12 Drug Administration Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license