4 Biopharmaceutical fundamentals of
technology satisfying the demands of therapy on a higher level had been established and enabled by biopharmacy. New generation pharmaceutical preparations developed on the basis of recent scientific achievements facilitated a significant progress in therapy by improving existing drug therapy methods and developing entirely new therapeutic facilities (e.g. compound preparations, controlled drug release systems, including autoregulatory and targeted release systems.)
The earlier active agent – pharmaceutical effect approach needs to be updated with the pharmaceutical preparation – pharmaceutical effect approach both for pharmacists and physicians, supplementing it with now available modern biopharmaceutical and drug therapy knowledge.
Modern pharmaceutical preparations (dosage forms) are likewise composed of active agents and excipients with a drug delivery function. However, owing to their specific composition, structure, in addition to introducing active agents in the body, they are also capable of optimizing drug therapy through altering the pharmacokinetic parameters of the active agents.
Drugs have two lives: one before administration, the other, in vivo, after administration. The first stage is there for the development and preparation of the drug, the second for the triggering of a therapeutic effect, the application of the drug. It is the harmonization of the administration of drug and the stages before and after administration that lead to the development of modern, biocompatible preparations and drug delivery systems. Both stages deserve examination and comparison from unit operation as well as biopharmaceutical aspect.
Regarding the primary purpose of pharmaceutical research and development or pharmaceutical production it manifests clearly that the in vivo part is dominant in the relationship of the two stages, where the first stage must fulfill the set of requirements defined by the stage after the administration of the drug with the utmost accuracy.
In the course of developing pharmaceutical technology, all the pharmacological, pharmacokinetic, physico-chemical, pharmacophysical, pharmacochemical and pharmaceutical technologic parameters of drugs (active agents and preparations) must be taken into consideration, which enables
introduction of active agents, pharmaceutical preparations into the body,
delivery of the preparation to the location of absorption,
control of active agent release and
exertion of the optimum therapeutic effect.
The dosage form, size, consistence, composition of the drug depend on the route of introduction.
Table 4-II.
Dosage forms and routes of administration
dosage form dosage mode in latin route of introduc-tion
tablet buccalis,sublingualis oral cavity
solution (gutta), emulsion, suspension
powder, granulate, tablet, capsule per os oral (ingestion)
Chapter 4: Biopharmaceutical fundamentals of pharmaceutical technology
dosage form dosage mode in latin route of introduc-tion
solution for injection
intra venam vein
intraarterialis artery intracardialis heart
epiduralis epidural space intraarticularis joint
intracutan skin
solution, emulsion, suspension for
injection intramuscularis muscle
solution, suspension for injection subcutan subcutaneous tissue solution, suspension intraperitonealis abdominal cavity solution, emulsion, suspension epicutan
skin
ointment dermalis
patch transdermalis
aerosol inhalatio (pulmonalis) bronchi and alveola
eye drops, eye ointment in
solution, suspension, emulsion conjuctivalis conjunctiva nasal drops, gel, spray in
solution, suspension, emulsion nasalis nasal cavity ear drops in solution, suspension oticularis ear
suppository, enema rectalis rectum
vaginal suppository, vaginal
tablet, globules vaginalis vagina
urethral sticks urethralis urethra
Getting the preparation to the location of effect may be achieved:
directly (local application), or
indirectly, assisted by vital functions (e.g. intestinal peristaltic, blood-stream, absorbing epithelial tissue).
In case of intravenous administration, the active agent is distributed in blood and, by the aid of the cardiovascular system, in tissues to achieve a systemic effect.
Knowledge of parameters of solubility, blending and distribution after immission in blood are necessary for drug design.
In case of intravenous administration, the drug is homogenized and distributed in the body without absorption shortly after administration. This happens much slower in case of intramuscular administration, due to absorption. The composition, pH and volume of blood is practically constant.
Fig. 4.1.
Schematic diagram of our cardiovascular system
From a technological and economic aspect it can be established that tablets are relatively easy and inexpensive to produce in mass quantities. Also, being so simple to administer, it is one of the most widely used dosage mode for peroral administration of macro size dosage forms.
From a biopharmaceutical and unit operations aspect our intestinal system is very diverse, rather complex and determined by several parameters, as required for the utilization of nutriments. According to its purpose, the anatomical structure of the intestinal system, its functional anatomical characteristics, different cytological structures, varying pH and enzyme composition of the internal fluids of its individual sections are fundamentally determining for the options of pharmaceutical therapy.
Fittingly with its consecutive structure, the processes occurring in individual sections of the GI tract are particularly significant, as they influence and in many cases prepare the functions and options of the subsequent intestinal sections.
Designing orally, perorally or rectally administered preparations the conditions that surround the preparation after administration need to be considered. Therefore, the body of knowledge of pharmacological technologists and even attending pharmacists
Chapter 4: Biopharmaceutical fundamentals of pharmaceutical technology
plays in therapy, how it exerts its effect or what are the possible risks of administering an inadequate quality (e.g. release, disintegration) preparation.
If the whole dissolution and adsorption process is considered, not just administration alone, it becomes clear that contrary to common belief, the simplicity of peroral dosing is ostensible. Considering only the facts that it does not require professionally trained staff, goes without the difficulties (e.g. intravenous administration, pain) and risks (e.g. infections) of giving injections, this dosage mode is truly simple. Actually, the process following the taking of a tablet is rather complicated and complex as the fate of the tablet inside the body is influenced by several voluntary and involuntary factors.
From a unit operations aspect, in peroral administration, at the start of the above mentioned second stage (i.e. subsequent to administration) the act of swallowing, for example, is a complex action, influenced by several parameters, controlled in different ways. There is voluntary control over the first phase of swallowing, thus it cannot be positively guaranteed that the patient will ingest the drug at the designated time. The patient has an active, decision-making role in adhering to the prescribed, recommended therapy with this dosage form. This subjective factor needs to be considered in therapy.
Cooperation in therapy is expressed by the term compliance, describing the level of precision on the patient’s side, the degree of adherence to prescriptions, which is a necessary condition of successful drug therapy. It is a common experience that little children protest the unusual, bitter taste of tablets. Others, often even adults, are averse to taking tablets due to personal conditions, incidental bad experience or illness, having difficulties with (or altogether incapable of) swallowing tablets, forget to take it, confuse different tablets or fail to thake the prescribed dose. If tablet ingestion is not a viable choice, or a difficulty, then splitting, crushing and flavoring of the tablet or substituting it with alternative dosage forms (e.g. effervescent tablet, soluble tablet or injection) is recommendable, unless otherwise contraindicated.
For biopharmaceutical reasons, to make swallowing easier, tablet shape is usually a flat cylinder or oblong with rounded edges in case of larger doses. Tablet size conforms to the dimensions of the pharynx and the esophagus.
Fig. 4.2.
Anatomical structure of swallowing conditions
Tablets, just like food, are transferred to the pharynx by the downward movement of the tongue root. As of the arrival of the tablet in the pharynx, there are no further voluntary means of influencing its course. In addition to overcoming the psychic inhibition, placing the tablet on the rear end of the tongue and swallowing with a head slightly leaned back can help.
Contracting pharyngeal muscles direct the tablet towards the dilated upper tract of the esophagus and prevent it from returning to the oral cavity. As a result of the peristaltic contractions of the esophagus the tablet enters the stomach through the cardia. This ring of muscles, made up of skeletal muscle fibers, acts as a sphincter, preventing gastric content from returning to the esophagus (reflux). The sphincter opens only if the peristaltic wave running along the esophagus arrives to it. This is when the tablet can enter the stomach through the opening cardia.
Liquid dosage forms pass through the esophagus faster than the peristaltic movement, pulled on by their own weight. However, they cannot enter the stomach before the esophageal peristalsis opens the sphincter.
For the ingested tablet entering the digestive system, the stomach has an important
“distributional”, controlling function beyond its absorptive ability. Depending on their design, drugs behave in various ways in the stomach:
1) disintegrate, releasing the active agent partially or fully, 2) do not disintegrate and active agent release begins,
3) being gastroretentive, form a depot in the stomach by expanding or clinging to the gastric mucosa, blocking passage,
4) pass on unchanged to the subsequent parts of the GI tract.
Motion of the gastric content is controlled by the antrum pyloricum. By using coatings dissolving in different pH levels matching the various pH conditions in the GI tract, a retarded or targeted release of active agents can be achieved. Active agents sensitive to the gastric fluid require the development of dosage forms with enteric coating (e.g. coated tablet, coated pellet). Depending on the location of effect (e.g.
enzymes) or the location of adsorption, active agent release can be controlled in the various sections of the small intestine in a planned manner, which significantly increases biological usefulness.
Non-absorbing expedients of pharmaceutical preparations used in the digestive system leave with the excreta. For injections and implants however it is advisable to use expedients that are present in the body anyway (e.g. water, phospholipids) or such polymers that are not toxic and break down in the body after a while.
Chapter 4: Biopharmaceutical fundamentals of pharmaceutical technology
Fig. 4.3.
The digestive system
The above examples show that in addition to therapeutic requirements, biopharmaceutical parameters have a direct effect on the applicable dosage forms, the parameters of the drug, applicable expedients and production technology.
Biocompatible novel macro, micro and nano size drug delivery systems are the significant of connection of pharmaceutical technology and biopharmacy, which base and allow the optimization of pharmaceutical therapy by harmonization of dosage, blood level controlled by time, administration route require to treatment, and time interval of pharmacological effect. This type of pharmaceutical preparation is able to release active substances in planned and useful way based on modified biopharmaceutical properties. This kind of liberation is allowed by manufacture technology and biopharmacy properties of preparation. Release of active substance has to be possibly tailored to properties of administration site. Due to intense development and research activities of the last decades, novel preparation is appeared, which is called internationally drug delivery systems (DDS). These biocompatible preparations allow the design and optimization of therapeutic effect in the aspect of dosage form, dosage, speed and site of drug delivery, plasma level and applied excipients. Biopharmaceutcial based improvement of therapeutic effect extends pharmaceutical therapy significantly.
Not only by having fewer side effects and less dosage, efficiency and tolerability of pharmaceutical treatment could be improved, but also there are possibilities for control of plasma level according to time and site of action. Basic requirement of development of DDS systems was the pharmaceutical technological view based on biopharmacy.
Connection of these two sciences enriched each other in the last three decades, and due to this new drug delivery systems have been created, which are able to control drug release in time and according to site of action. These preparations are capable for continuous, discontinuous, accelerated, sustained, delayed drug delivery or which are controlled externally or self-control drug release due to safe and changeable dissolution profile, mechanism of drug delivery and programmability.
Questions
1) What is the difference between ADME and LADME systems?
2) What are the main aspects to be taken into consideration for pharmaceutical prepa-ration design?
3) What are the requirements for product biocompatibility?
4) What are the advantages and disadvantages of peroral administration?
5) What compounds belong to class II. BCS?
6) What compounds belong to class III. BCS?
7) List the main characteristics of drug delivery systems!
References
Kelley, B. D: Validation of Biopharmaceutical Manufacturing Processes, American Chemical Society Division of Biochemical Technology Calif, American Chemical So-ciety Meeting San Francisco, 1997.
Ritschel,W.A., Kearns,G.L.: Handbook of basic pharmacokinetics: including clinical applications, 5th ed, Washington, American Pharmaceutical Association, 1999.
Panchagnula, R., Thomas, N.S.: Biopharmaceutics and pharmacokinetics in drug re-search, Int. J. Pharm., 201, 131-150, 2000.
Brandys, J.: Drug therapy: safety, effectiveness, and economics, Przegl Lek, 58, 226-229, 2001.
Aulton M.,E.: The Design and Manufacture of Medicines, Elsevier, New York, 2007.
Recommended websites
http://www.particlesciences.com/docs/technical_briefs/TB_2011_9.pdf http://69.20.123.154/services/bcs/search.cfm
http://www.understandingnano.com/medicine.html http://www.youtube.com/watch?v=kxSX6YJTS2I