药物制剂剂型设计高级教程(英)

INDUSTRIAL PHARMACY: PHARMACEUTICAL DOSAGE FORM DESIGNGRADUATE COURSE IN PHARMACEUTICSCREDIT: 3 Hours1PHARMACEUTICAL DOSAGE FORM DESIGN (3)1.1INTRODUCTION (3)1.2AIMS AND OBJECTIVES OF THE COURSE (3)1.3OBJECTIVES OF INDIVIDUAL STUDY UNITS (4)1.3.1Review and study of the different phases of product development (4)1.3.2Principles and factors of importance during development, productionand quality assurance of conventional dosage forms (6)1.3.3Oral dosage forms (7)1.3.4Parenteral dosage forms (10)1.3.5Design of dosage forms for topical and local drug delivery systems (13)1.3.6Pharmaceutical aerosol products (14)1.3.7Rectal and vaginal suppositories (15)1.3.8Novel dosage forms and biotechnology (16)1.4ASSIGNMENTS (17)1.5REFERENCES (18)1.6Study Guide compiled by: (19)1 PHARMACEUTICAL DOSAGE FORM DESIGN1.1 INTRODUCTIONTo manufacture a pharmaceutical dosage form, it is necessary to combine the unique properties of the drug with the unique properties of the specific dosage form as well as quality control requirements. The whole process starts with the development and clinical evaluation of the substance, proceeds via a preformulation phase for the drug and ends with the dosage form, which may be produced industrially after the necessary scale up procedures.In this study guide the material that a student will have to manage to successfully complete the course Pharmaceutical Dosage Form Design as part of the Ph.D. in Pharmaceutics is outlined. It describes the aims and objectives of the course and gives information about the study material that the student will have to use.1.2 AIMS AND OBJECTIVES OF THE COURSEThe aim of this course is to enable the successful student to recognise and understand the development process for pharmaceutical delivery systems that are therapeutically effective, bioavailable, safe and elegant. The objective is to study the different phases in the development of a dosage form. The different phases for conventional dosage forms include the stages in which the substance drug is clinically tested, formulated, manufactured and the quality control procedures related to each stage. Dosage form development using biotechnology and targeted dosage forms will also be studied.On successful completion of the course, the student should have acquired the necessary background and understanding of the development process for pharmaceutical products so that he/she could, through innovative thoughts and scientific reasoning, design and evaluate new innovative pharmaceutical products.1.3 OBJECTIVES OF INDIVIDUAL STUDY UNITSThe course is divided into the following three study units each with its own study objectives and assignments, i.e.:1. Review and study of the different phases of product development,2. General formulation factors and procedures, principles and factors ofimportance during development, production and quality assurance of conventional dosage forms, and3. Alternative and/or targeted dosage forms and biotechnological products.1.3.1 Review and study of the different phases of product developmentThe first step in the research process of drugs is the scientific investigation and study of the specific illness in order to form research teams whose work will lead to the invention and development of new chemical entities with efficient actions.Research teams in industry are multi-disciplinary and are composed of experts from different scientific fields like chemistry, biochemistry, physics, statistics, medicine, pharmacology, pharmaceutics, physiology, microbiology, etc. The main objective of research is to produce safe drugs that may be preventative, curative or alleviate.Subordinate objectives are:1. to understand the molecular basis of biological mechanisms for sick and healthypersons;2. to develop new biological test methods;3. to develop a quantitative understanding of the physical, chemical andphysiological interactions of drugs with biological systems which may lead to new drug design;4. to understand absorption, transfer and action of a drug;5. to develop drugs with low toxicity, reproducible action and high specificity for agiven pathological condition, and6. to develop cost-effective drugs.The processes of research follows a certain flow pattern for which planning is the starting point; this is followed by laboratory scale synthesis, pharmacological and toxicological selection, patent protection, phases I and II pre-clinical development and testing and the three phases of clinical testing and registration.The estimated cost for the development of a new drug is approximately $500 million and takes on average between 8 and 15 years. The chance for success is 1 : 8 000 - 10 000 and marketing success approximately 25 %. It is therefore of cardinal importance that high productivity and high effectiveness be the criterion of research because of the high costs involved. Expertise is therefore a prerequisite to be successful in the field of pharmaceutical research.1.3.1.1 Objectives and outcomes for this study unitThe student must have a broad base of knowledge of the different phases of drug design, testing and product development in order to contribute in a development team and to evaluate the different facets of the process. In the context of this course it is not expected of the student to become an expert on any specific aspect but he/she must rather acquire a broad general working knowledge.The student must be able to:1. Understand the essential aspects of a development plan for a new product.2. Understand the different phases in the development process of a new drugand be able to describe its essential facets.3. Understand all the considerations and phases of a multidisciplinary approachto formulation and dosage form development.1.3.2 Principles and factors of importance during development, production andquality assurance of conventional dosage formsThe student must be able to recognise the distinctive properties to be taken into account for the development of a conventional dosage form:a. a motivation of the choice of dosage form;b. a general formula;c. the specific manufacturing steps and processes;d. precautionary measures and tests to ensure the quality of the product, ande. test to control the quality.The following are meant with conventional dosage forms:1. Oral dosage forms1.1 Tablets and hard capsules, solutions, emulsions, suspensions, oralsustained release products.2. Parenteral dosage forms2.1 Injections, large volume parenterals, suspensions for injection.3. Dosage forms for local application3.1 Ointments, creams and gels.4. Vaginal dosage forms5. Suppositoriesproducts6. Aerosol1.3.3 Oral dosage formsIn this division of pharmaceutical dosage forms, it is presumed that the choice of route of application had already been made and that the oral route had been chosen (not the other routes such as transdermal, rectal, parenteral, etc.). This choice would have been made taking many factors into account, such as: physical and chemical properties of the drug, type of effect desired, type of illness to be treated, speed of action, duration of action, pharmacokinetic parameters, etc.Oral dosage forms focus is on all dosage forms taken orally for a local effect in the mouth, throat or gastrointestinal tract or for a systemic effect in the body after absorption from the mouth or gastrointestinal tract.Oral dosage forms can be divided into two main groups on the grounds of the physical state of the dosage form during consumption, i.e. solid oral dosage forms (tablets, capsules or powders) and liquid oral dosage forms (solutions, syrups, emulsions and powders for suspensions).Three steps are distinguished during the development of oral dosage forms, i.e.:1. the choice of the type of dosage form;2. the formulation and manufacture thereof, and3. the evaluation and control of the quality of the product.In order to develop oral products it is necessary to know specific properties and characteristics of this type of dosage form. This guide will help student get this knowledge or to refresh their memories.1.3.3.1 Outcomes: Choice of the type of oral dosage formStudents must be able to give an opinion (with the necessary motivations) on the choice of the type of dosage form for a specific drug taking into account preformulation data at their disposal.The choice of the type of dosage form rests on the one hand on the type of effect required (i.e. speed of action, duration of action, blood concentrations and pharmacokinetic parameters) and on the other hand on physicochemical properties and required dosage of the drug. Physicochemical properties of importance include: physical form of the drug (liquid or solid), solubility in the presence of moisture and heat, taste, flow and compressibility properties, etc.1.3.3.2 Outcomes: Formulation and manufacture of oral dosage formsIn the case of oral solid dosage forms (especially tablets), the choice of the method of manufacture has a specific influence on the composition of the formula. The primary aim during preparation of mixtures for tabletting is to ensure good flow and compressibility properties whereas mixtures for encapsulation must mainly possess good flow properties.Drug-related properties that may influence the choice of method of manufacture of solid oral dosage forms include: Flow and compressibility, dose size and chemical stability. In the case of liquid oral dosage forms the solubility, dose size and drug（辅料）stability play a major role.The combination of drug(s) and excipients plays an important role in the physical and chemical properties of the final product and determines to a great extent the final quality and effectiveness of the product.1. In the case of liquid oral dosage forms the choice of excipients rests mainly ontwo requirements, i.e. (1) ensuring maximum physical and chemical product stability and (2) ensuring acceptable organoleptic product properties (i.e. taste, colour, consistency, etc.)2. In the case of solid dosage forms the choice of excipients is determined byfactors such as: the type of product and effect required. The chosen method of manufacture, and the influence of excipients on the flow and compressibility properties of the mixture/granulate. The acquirement of/and assurance of good tabletting properties (exclusion of tabletting problems such as laminating, capping, punch and the adhesion, etc. In general the inclusion of excipients must contribute positively to the quality and effectiveness of the final product.Students must be able to make knowledgeable contributions with regard to composition of formulas for a chosen oral dosage form as well as the decision on the method of manufacture considering the available preformulation data. They must also be able to identify problems during tabletting and relate these to problems during formulation and/or manufacture and be able to recommend remedial actions.1.3.3.3 Outcomes: Evaluation of oral dosage formsIn-process evaluation as well as evaluation of the final product is necessary in order to ensure that the product received by the patient complies with all requirements with regard to quality (assay), effectiveness and safety. In-process evaluation is aimed at discovering and solving formulation and manufacturing problems as soon as possible, whereas the aim of final product evaluation is to ensure quality effectiveness and safety of the product.The tests mentioned must entail the determination of physical properties and assay of the product and comparing these with official requirements or standards (including shelf-life and expire date in the final package with the aid of accelerated and long term stability trials). From the formulator's viewpoint, it is important to keep the following in mind: Quality is built into a product through good manufacturing and laboratory practices; it cannot be tested into the product!Students must be able to point to and motivate the in-process evaluation tests for the chosen dosage form. To identify and motivate the times during which these tests must be done, motivate the different evaluation tests on the final product, be able toevaluate the results of these tests and be able to make relevant conclusions from the data.1.3.4 Parenteral dosage formsThe therapeutic effectiveness, biological availability and safety valid for all pharmaceutical dosage forms are also applicable to parenteral dosage forms. Seeing that the highly effective first line of body defence, i.e. the skin and mucus membranes is bypassed during application of parenteral dosage forms, a number of unique demands and considerations are to be met, i.e.:1. Sterility.2. Product must be free of foreign particles.3. Absence of pyrogens.4. Choice of raw materials, solvents and excipients. The choice of raw materials,solvents and excipients is limited. Toxicity and irritating properties of many raw materials limit their choice in parenteral dosage forms. For the same reasons pH and isotonicity are also of importance in the case of these products.5. Choice of packaging materials. Because of the inmate contact of parenteralcomponents with packaging material and because of the fact that these products as water solutions are subjected to high temperatures during sterilisation, the packaging material may have a large influence on the physiological acceptability or stability of the product. For these reasons different pharmacopoeia specify specific requirements for packaging materials for sterile products.6. The product must be non-toxic, non-irritating and not sensitising.7. Stability. Drugs and excipients are mostly in solution or in any case in contactwith water and the product is subjected to sterilisation processes such asheating, ionising, radiation, gas sterilisation, etc. which may enhance breakdown reactions. These breakdown reactions may in turn lead to toxicity, irritating properties and can in certain instances cause physical contamination.8. Physiological factors, i.e. absorption, irritation, etc.All activities or actions, be they at the industrial, dispensing or application level, are aimed at the incorporation and preservation of these properties in the product. These properties must be built into the product during manufacturing processes and maintained by formulation, packaging and storage. It is the duty of the Industrial pharmacist, be it in his own capacity or in conjunction with other members of the product development team, to ensure these properties.In case of the industrial pharmacist, the duty entails the following:* Knowledge of the formulation and composition of different physical forms of parenteral products.* Unique and differentiating properties of this dosage form and the quality control measures applicable.In order to satisfy the aims the student must renew his knowledge of the theoretical principles emphasised below with the use of the given references in order to be able to apply these in practice during the formulation or planning of parenteral dosage forms.1.3.4.1 Outcomes: The influence of pharmaceutical and biological factors inparenteral formulation and applicationThe student must be able to integrate the different factors having an influence on formulation and manufacture of parenteral dosage forms into the product development process.1. The chemical and physical properties of drug and excipients.2. The requirements for raw material and packaging material.3. The volume of the injection.4. The purpose of the preparation.5. The route of application and the biopharmaceutical parameters involved.1.3.4.2 Outcomes: The composition and properties of/and requirements for thedifferent physical forms of parenteral dosage formsThe student must know the basic composition and properties as well as the methods of manufacture and requirements of the different physical forms of injectables and must be able to convert these into the whole product development process.solutions.1. Parenteralsuspensions.2. Parenteralemulsions.3. Parenteralproducts.4. Freeze-dried5. Large volume parenteral solutions.The following factors are of special importance:1. Excipients and how this relates to the route of application.2. Toxicity and irritation potential.3. The role of pH.4. Stabilization.5. Sterilizationmethods.6. Particle or drop size where applicable.1.3.5 Design of dosage forms for topical and local drug delivery systemsDosage forms for topical and local application cover a wide variety of dosage forms, i.e. liquids (solutions, emulsions and suspensions), semi-solid preparations (ointments and pastes) and powders. The most important function of skin preparations is protection against external influences, concentration of actives in the skin to effect healing and absorption of the active ingredient through the skin to give a systemic action.The effectiveness of preparations for local application is influenced by the following properties of the active ingredient: concentration, solubility, distribution coefficient, dissolution rate as determined by the physical form of the drug (i.e. particle size, surface, etc.) and permeability inside or through the skin. The second important factor determining the effectiveness of preparations for local application is the condition of the skin, i.e. water content, degree of injury of skin surface, place of application, treated skin surface, pre-treatment of skin and age of patient.The topical carrier material affects contact between skin and active ingredient. The goal of the carrier material is to ensure the effectiveness of the active ingredient. Important properties of dosage forms for local application are that it must be non-irritating or sensitising, cosmetically acceptable, stable and easy to apply.The biological activity of a topically applied application is mainly dependent on the rate of release from the carrier and penetration into the skin. While formulating preparations for local application, it must also be kept in mind that irritation or sensitisation of the skin must be prevented. The release of the active ingredient form the carrier and more specifically the rate of release as well as biological activity is dependent on:* the chemical structure of the drug;* the physical state of the drug;* the type of dosage form;* the presence/absence of penetration enhances, and* the pharmaceutical manufacturing procedure.Changes in the physical properties of a preparation can enhance the diffusion of theactive from carrier into the skin. Factors enhancing release from the carrier include ahigh active ingredient concentration in order to get a high carrier-skin concentration gradient, a high activity coefficient in the carrier to enhance release and a favourable distribution coefficient between carrier and the skin.1.3.5.1 Objectives and outcomes for topical and local delivery systemsThe student must know the basic composition and properties as well as the methodsof manufacture and requirements of the different physical forms of topical dosageforms and must be able to convert these into the whole product development process.1.3.6 Pharmaceutical aerosol productsAerosol products are unique delivery systems since they contain a propellant(s) toforce the product out of the container in the required form and quantity that are necessary. The product contains the drug that may be formulated in a solution, emulsion or suspension. The propellant either can be liquefied or compressed gases.Aerosol products can be used to deliver drugs for local action (on skin, in the noseand lungs) or systemic action where it is also applied via the nose and lungs. In the瓣膜case of aerosol products for local application it is supplied with valves enabling theuser to determine the amount marked off or released. In the case of inhalation aerosol products, a specific quantity is released each time the valve is activated.The principles of formulation of solutions, emulsions or suspensions are applicable inthis case but the influence of the propellant on the stability of the product must betaken into account.1.3.6.1 Objectives and outcomes for aerosol productsThe following aspects are important for the student to know about the formulation of aerosol products:1. Which propellants - compressed and liquefied gases;2. Different valve systems - continuous spray and soigné;3. Different containers for products - glass, metal or synthetic material;4. What kind of action of aerosol products - foam, spray or solid stream products;5. Which factors influencing the particle size in case of inhalation aerosolproducts;6. Typical formula for a suspension inhalation aerosol product and a local solutionaerosol product, and7. Method of manufacture - schematic diagram.1.3.7 Rectal and vaginal suppositoriesTwo kinds of suppositories are most often formulated:1. Rectal suppositories: The formulation of rectal suppositories is basically thesame as that of suspensions, solutions and emulsions with a special carrier medium (the base) which is solid at room temperature but which melts at body temperature and/or dissolves in rectal fluids. The purpose is to deliver drugs for either local or systemic action.2. Vaginal suppositories: Vaginal suppositories are formulated in the same wayas solution tablets or solution suppositories. The purpose is only for local action.Apart from solid forms, liquid forms are also used for both rectal and vaginal application, i.e. enemas and irrigation solutions ("douches"). In the case of semi-solid dosage forms, the types of base used are important for effectiveness.1.3.7.1 Objectives and outcomes for suppositoriesAspects of importance with regard to these dosage forms that the student must know and understand are:1. Physiology and anatomy of the route used for application of the dosage forms.2. The properties of suppository based available,3. The differences in formulation of water soluble and water insoluble drugs insuppositories,4. Quality assurance tests that must be carried out on rectal and vaginalsuppositories.1.3.8 Novel dosage forms and biotechnologyNew ways to deliver drugs and unique ways to target and/or localise it at target areas in the patient's body are discovered almost weekly. It is mainly done to make dosage easier, more effective and to get fewer side effects. Technological developments make it possible to realise new and innovative delivery methods and systems.1.3.8.1 Aims and objectives for novel drug deliveryThe student must have the necessary knowledge of the principles by which drugs are targeted, localised and automatically delivered and must know how the dosage forms are formulated and manufactured. After studying this subject, the student must be able to describe and give the methods of manufacture of these new drug delivery systems. They should also be able recognise the potential use of new and innovativedrugs such as proteins, peptides etc. and be able to propose suitable dosage forms and delivery systems for these drugs.1.4 ASSIGNMENTSThe following assignments must be completed:1. Give an overview of the essential aspects (different phases) of a developmentplan for a new pharmaceutical product.2. Write in three pages a protocol for the development of an aspirin effervescenttablet. The object being to produce a clear solution after effervescence.3. You must formulate a proposal for the formulation of a benzodiazepine(diazepam) injection. Reason and supply reasons for differences in considerations and formulas when an intramuscular or an intravenous injection must be prepared.4. You are instructed to formulate a Tetracaine HCl preparation for localapplication. Reason out and supply the reasons (with the necessary references) for your considerations during formulation. Give the differences in considerations and the formula when you were to prepare a gel, ointment or cream. Give the specification for raw materials, motivation for inclusion of excipients and quality control measures that must be met during the product development process for this product.5. You must formulate an inhalation aerosol product of salbutamol in either asuspension or a solution system. You must use non-fluorinated propellants.Give a motivation for your formulae and give the quality assurance tests that you will do on the final product.6. You must formulate a suppository of cyclizine hydrochloride. Give a motivationfor your formula and supply the quality assurance tests that you will perform during the development phase and on the final product.7. Give the basic principles of the methods of delivery, the manufacturingmethods and the quality control procedures applicable for a new non-traditional drug delivery system of your choice (approximately 3 pages typed).Completed assignments must demonstrate that the student understands the course material and is able to apply the knowledge in practice. During the evaluation of assignments, focus will be placed on assessing the originality of answers, correct interpretation of the problem, and applicability of the student’s approach.When doing the assignments concentrate on getting the information from the references listed at the end of this study guide.1.5 REFERENCESPrerequisiteThe student must have a thorough knowledge of the different types of dosage forms, the formulation thereof and the production processes unique to a specific dosage form.Prescribed work1. Lachman, L., Liebermann, H.A. & Konig, J.L. 1986. The theory and practice ofindustrial pharmacy, 3rd ed., Chapter 5 to 21.Other works that may be consulted1. AULTON, M.E. 1988. Pharmaceutics: the science of dosage form design.Churchill Livingstone : Edinburg.2. BANKER, G.S. & RHODES, C.T. 1990. Chapters 8 - 12 & 16. ModernPharmaceutics. 2nd edition. Marcel Dekker : New York.3. BARTLING, D. & HADAMICK, H. 1990. Development of a drug - its long wayfrom laboratory to patient. Darmstadt, Germany.4. OSBORNE, D.W. & AMANN, A.H. 1990. Topical drug delivery formulations.New York : Marcel Dekker Inc. p. 1-12; 197-211.1.6 STUDY GUIDE COMPILED BY:Melgardt M. de Villiers, Ph.D., Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71209, E-mail: devilliers@.。