Hi-tech tablets – why and what for? 1
Dr. Medvedev O.S., MD, PhD, Dr. Medveva N.A., MS, PhD
Lomonosov Moscow State University
Every year drug treatment obtains more and more significance in the general totality of
all medical assistance and treatment, appearing as a cheap alternative to the invasive surgery and
hospitalization [1]. The widespread use of the drug medications, vitamins, food supplements is
concerned with different factors: the creation of new, effective drugs; production of well-known
preparations in new dosage forms which decrease the risk of the adverse effects development;
active advertising of the preparations among physicians and direct advertising among patients;
special accent on the desease prevention.
The creation of the new drugs becomes more and more expensive and related to big
financial risks. Total expenses of the pharmaceutical companies in the US for drug development
rise in the geometric series, and come to $ 618 millions in 1970, 1 917 in 1980, 8 420 in 1990,
26 031 in 2000 and 33 215 in 2003. In spite of the gigantic expenses, the quantity of new
developed drugs appearing on the market does not increase, vice versa, it has a tendency to come
down. Thus, in 1996 FDA (Food and Drug Administartion, USA) approved 53 new drugs, while
in 2003 – only 21 [2]. Because of the decrease of efficacy of the research in the area of
developing new drugs, more attention is paid to the improvement of the properties of already
known drugs, either ones that are covered by patent or those that are generic (the drugs whose
patent is over). The cost of the generic drugs is only 15 – 20% of the patented drug cost, which
leads to the increase of their share on the pharmaceutical market [3]. Hence, the totality of
objective factors – the decrease of the developmental efficacy of the fundamentally new drugs,
high risks of the long duration investment in this area, the presence of big diversity of cheap and
sufficiently effective generics – is the motive power that stimulates the development of the new
dosage forms of already widespread medications [4].
The area of the pharmaceutical research could be divided into two big parts –
pharmacokinetics and pharmacodynamics, that is the influence of the body upon the drug and the
influence the drug upon the body, respectively. It is obvious that it is impossible to change the
pharmacodynamic characteristics of the drug, because it depends only on its chemical structure
which should be left unmodified in any dosage form, any covering or any form of drug
consumption. The only possibility is to change the pharmacokinetic characteristics, e.g. the
speed or place of absorbtion, bioequivalence and metabolism in the digestive system.
The development of the new ways of administration allows to breathe new life into wellknown medications due to the overcoming the pharmacokinetic limitations of the standard forms.
The systems with the regulated speed and characteristics of drug release have additional benefits
in comparison to standard tablets, first of all due to the decrease of intake frequency during the
day and enhace of the patient’s compliance, the decrease of the concentration fluctuation in
blood and its maintaining within the wishful limits, the localization of the excretion and the
decrease of the adverse event risks.
All these characteristics to a greater or lesser extent could be modified for those drugs
that are administered both in parenteral and oral way. In this article we, above all, will review the
modifications of the dosage forms for the oral drugs, as the most convenient and most frequently
used, espessially at home. For orally administered drugs it is possible to modify the speed of the
drug release from the tablet (drop, capsule), the place of the excretion from the digestive tract,
the duration of its presence in the particular area of the digestive tract (within the limits) which
as a result would determine the speed of absorbtion, the degree of passing through the portal vein
and the dynamics of blood concentrations. The classification of all the dosage forms is wellknown [5]. In our review we will introduce the latest achievements in this area.
___________________________________
1
This article was published in the “Difficult Patient” (Трудный пациент), #6, 2005.
The drugs differ in their pharmacokinetic properties. Some of them obtain ideal
characteristics for absorbtion as they go through the digestive system, others do not. The
Biopharmaceutical Classification System, approved by the FDA in 1995, subdivides all the
pharmaceutical substances depending on their dissolubility and permeability in the intestines.
The I class unites the preparations that obtain a very high level of dissolubility and consequently
are well absorbed during the oral intake. All other substances (II – IV classes) are characterized
either by poor dissolubility or by poor permeability, or the combination of both (see Figure 1).
Such preparations have problems with bioavailability while taking per os [6].
Permeability in the
intestines Reff. (x10-1) cm/s
10
Class I
Class II
Verapamil (calcium ion antagonist)
Propranolol (non-selective betablocker)
Metoprolol (selective beta1-receptor
blocker)
Ketoprofen (NSAID)
Naproxen (NSAID)
Class III
Class IV
Ranitidine (histamine H2-receptor
antagonist)
Cimetidine (histamine H2-receptor
antagonist)
Atenolol (beta-blocker)
Hydrochlorothyazide (diuretic)
Furosemide (loop diuretic)
1
0.1
0.01
1
Figure 1
10 000
10
100
1 000
Volume of liquid (ml), necessary for dissolving of the maximum
allowed dosage at the minimum dissolubility (pH in the limits of 1to 8)
100 000
Biopharmaceutical classification of drugs; preparations, typical for each class.
On the table of major properties of different parts of the digestive system (Table 1) that
influence the dissolubility of drugs, the time of passing of the food lump or a drug through the
particular section of the digestion tract (“absorbtion window”) has a special significance, along
with the comparative surface area (though we can not change it) [6]. New technology gives us a
possibility to respond to the demand of the clinicians who administrate oral drugs.
Controlled speed of the drug entrance in the digestive system
For the preparations of the I class it is necessary to exclude the peak concentrations in the
blood that is achieved by the developing of tablets with regulated speed of drug release in the
digestive system.
In the 1970 – 1980’s the investigators realized the necessity to develop the systems for
flat (even) profile of the drug release in the gleam of the digestive system, which prevents the
developing of the adverse events that are concerned with the high, peak concentrations of the
drug [7,8]. The example could be a new dosage form of the well-known nifedipine (Procardia
XL, Pfizer), a drug that is used in the cardiology. A solution of nifedipine is placed in the
Table 1
Physiological piculiarities of different parts of the digestive system and absorbtion of the
medical products.
pH
Membrane
Blood supply
Surface area
Time of
passing
through
Mouth
approx. 7
thin
small
brief, if the
special
dosage forms
are not used
Oesophagus
5 -6
small
brief
-
Stomach
1–3
digestion,
absorbtion of
the weak
acids
6 – 6.5
bile-duct,
properties of
the surfaceactive
substance
7 -8
very thick,
virtually no
absorbtion
normal
very good,
quick
absorbtion
even of small
doses
-
good
small
30 – 40 min,
with a
reduced
absorbtion
no
normal
good
small
very brief (15
min),
“absorbtion
window”
no
normal
good
approx. 3
hours
no
-
good
very large 3 –
5m, 80
cm2/cm
not very large
1.5 – 2m
up to 24 hours
lowest part of
the large
intestine and
rectum, yes
Duodenum
Small
intestine
Large
intestine
5.5 - 7
Passing
beyond the
liver portal
system
yes
capsule, from which it is released evenly due to the osmotic entrance of the fluid into the capsule
(oral osmotic – OROS) (see Figure 2). In the 1990’s this kind of OROS-system was used for the
number of drugs: antimuscarinic preparation of oxybutynin chloride (Ditropan XL, OrthoMcNeil); used for treatment of the urinary bladder hyperactivity or psychostimulant
methylphenidate (Concerta, ALZA). The use of the OROS technology made it possible to
prevent the development of the mouth dryness which is typical during the administartion of the
oxybutynin [9,10]. In case of methylphenidate the increase of the excretion speed was achieved,
which was made for overcoming the tolerance to this drug (Figure 2).
A. System “pull-push”
B. L-osmotic system for oral use
Opening for drug
release
Semipermeable
membrane
Drug-containing
osmotic core
Polimer zone that
pushes out the
drug
C. three-layer system
Opening for the
drug release
Opening for the
drug release
Membrane that
determines the
speed
Osmotic layer that
pushes out the drug
Inner separating
membrane
Membrane that
determines the
speed
Drug #1
Drug #2
Drug solution
Drug #3
Soft gelatine
capsule
Figure 2
System with a regulated release of the drug on the base of osmosis.
External covering
L-OROS systems were specially designed for the administartion of the drugs that are
poorly permeating through the membranes of the digestive tract (Figure 2B). As an addition to
the technology of the osmosis pump (OROS), was developed the technology called Geomatrix
(SkyePharma), which is based on the use of the several covering layers on the tablet with a
barrier of highly tough hydroxypropylmethylcellulose (HPMC). In the center of this tablet is an
active substance (or substances), covered with one or more layers of polymer that controlls the
diffusion speed (see Figure 3) [11-14]. The tablets with different speed of drug release could be
produced using chemical components that differ in the speed of swelling, gel formation or
decomposition. During the dissolving process, the swelling barrier starts to thicken but does not
destroy, whereas the destroying barrier, gradually breaking apart, opens the core of the tablet
which leads to the controlled release of the active ingredient. Geomatrix technology was used for
the development of new dosage forms for those medications that were previously used only as
quickly dissociating tablets. For example, it was diltiazem HCl (Dilacor XR, Watson Labs),
paroxetin (Paxil CR, GlaxoSmithKline) and sodium salt of diclofenac (Voltaren XR, Novartis).
Figure 3
Multiple layer tablets (Geomatrix technology).
Another dosage form – spheroid system for oral intake (SODAS, Elan) was developed
with the use of the particles with the controlled release of the drug. SODAS technology could be
tuned for immediate release of the drug, for extended release or “pulse” release. The technology
is based on the use of spheric particles with a diameter of 1 – 2 mm, that contain the drug and
coated with drug-specific polymer that provides the regulated release. Polymers may be soluble
or insoluble and form a membrane around each sphere determining the the speed of the drug
release. The controlled release starts when the soluble polymer washes off in the medium, the
fluids flows into the core of the sphere, dissolves it, whereupon the the drug starts to diffuse. The
SODAS technology was used for developing such medications as diltiazem (Cardize LA,
Bioavail), methylphenidate (Ritalin LA, Novartis) [15], and morphine sulfate (Avinza, Ligand)
[16]. It is necessary to emphasize that the general limitation for all the tablets that possess a
controlled speed of release is the term of going out of the main dose (better all the dose) during
the time of its going through the stomach and small intestine (approximately 4 – 5 hours), since
in the large intestine the speed of absorbtion is much lower.
Prolongation of presence of the drug over the “absorbtion window”
The bioavailability of the preparation, which mainly absorbs in the upper part of the
digestive system, will depend on the factors that change the time of going through of food or
preparation. For example, after the food intake, the time of stomach evacuation rise, threfore it
prolongs the retention of the drug over the absorbtion window; as a result, the bioavailability
grows. Some food components – fats, a number of aminoacids, and peptides are known for
inhibiting the stomach evacuation and and intestine peristalsis [17,18].
In theory, the elegant and simple way to improve the absorbtion of the drug, could be
“fixation”, retention of the tablet with a controlled speed of an active ingredient over the
absorbtion window. This could be applicable for such preparations as Acyclovir, Captopril,
Furosemide, Metformin, Gabapentin, Levodopa, Baclofen, Ciprofloxacin [19].
The retention of the drugs in the stomach
The dream of drug developers stay the systems for prolonged retention in the stomach
(without food), that could have been safe and effective, – so-called gastroretention. One
approach is based on the use of microparticles with bioadhesive properties that quite often have
an ability to float on the top of the stomach contents (Figure 4) [19]. Microparticles are usually
coated with chitosan, which due to its positive charge binds with the elements of the mucous
membrane.
Microspheres float on the top of the
stomach contents
Microspheres adhere to the stomach walls after the stomach
evacuation
The capsule that contains bioadhesive microspheres is taken with water; the released microspheres float on
the top of the stomach cavity. As the contents of the stomach evacuates, part of the microspheres adheres to
the wall and continue to release the drug.
Figure 4
Assumed mechanism of the biodhesive microspheres retention in the human stomach.
Another way to detain the tablets in the stomach is the use of capsules that swell up to 15
– 20 mm in diameter and release the drug in series. Such boluses do not leave the stomach even
after the gastric phase of the digestion, because the opening of the pyloric sphincter does not
exceed 15 mm.
Absorbtion boosters
The absorbtion of those oral medicines that possess low permeability characteristics may
be improved by using the absorbtion booster (intensifier). Those are substances that temporarily
modify the tight junctions (intercellular contacts) between the epithelial cells of the intestinal
fibers [20]. It is interesting that many surfactants are able to enhace bioavailability. This is
esspecially applicable for polar substances such as proteins and peptides.
Release of the drug in the particular part of the digestive system
At present time other systems of the drug delivery are investigated, for example, a
multicomponent system which combines the pH-sensible properties and specific biodegradability
of the delivery of metronidazole in the large intestine [21]. In this new system the microspheres
of chitosan were obtained from the emulsion of the soluble paraffin as the external phase and the
solution of chitosan in the acetic acid as dispersed phase. The chitosan microspheres were
incapsulated inside the microspheres from Eudragit (Pharma Polymers), thereby forming the
multi-reservoir and pH-sensible system. In the animal experiment (rats) the medical substance
was not released in the acid media however it was released in the large intestine thus indicating
the susceptibility of the chitosan matrix to the intestine enzyme action [30].
For the research of the detailed characteristics of the new medical substances’
pharmacokinetics, Innovative Devices (URL) developed a radio-controlled “tablet” – IntelliSite,
that represents a special capsule of 10 mm in diameter and 35 mm in length [22]. Before the
intake of the capsule by the volunteer, it is loaded with soluble or powder drug (see Figure 5).
The passing of the capsule through the digestive tract is controlled in gamma-chamber. When the
capsule reaches the part of the intestine where the absorbtion process is starting, the holes in the
capsule open distantly by the external generator of the alternating magnetic field, and the
contents of the capsule releases. Every capsule costs $1200, therefore the research is quite
expensive. It could be presumed that in the future more cheap devices would be developed, that
would not need radiological equipment for the capsule localization and would be used for real
patient treatment.
Outward appearance
of the capsule
Lid with radioisotope mark
Electronic module for opening
the reservoir with drug
Inner rotary part
External part of
the capsule
Holes for release of the
drug
Stopper for infilling the reservoir of
the capsule with solution
Figure 5
Capsule for solution delivery.
As a result, one may observe a tremendous progress in the development of the devices for drug
delivery. But how far are the questions of modern therapy and pharmacology solved, from the
standpoint of the last achievements of pharmaceutics? It is obvious that when we talk about
administration of one or two medicines, we can significantly improve their bioavailability and
reach more even concentrations in the blood by using the dosage forms with controlled release.
The development of the “ideal” dosage form for numerous preparations taken simultaneously
even with the use of modern pharmaceutical technologies is doubtful. As an example, it could be
vitamin-mineral complexes, separate components of which may interfere on the chemical level
outside the body and mutually depress the absorbtion due to the competition for the absorbtion
sites on the carrier in the intestine epithelium [23].
For the solving of this problem the author suggests a simple method – a division of the
daily dose of the necessary elements into several tablets that could be taken in certain time
interval. This would allow to avoid the undesirable interactions and increase the positive effects.
Wouldn’t this scheme diminish the compliance of the patients? One of the causes of the
development of the prolonged preparations was a wish to reduce a number of the intakes to once
a day; the aim was to increase the patient’s compliance (“once-a-day is best”) [24]. In opinion of
Urquhart [25], this could be a good example of triumph of popularization over objective data. In
spite of the fact that this article was frequently cited for advertising purposes, afterwards the data
of Gatley [24] was scarified [26 – 28]. The reseach with electronic monitoring did not reveal any
significant differences in the compliance of the patients who took the preparation once or twice a
day [29].
Thus, the analysis of the scientific literature does not contradict the co-existence of the hitech methods of drug delivery and traditional 2-3 times-a-day intakes, if the pharmacokinetic
presuppositions are present, which are determined by their ingredients and the mechanism of
absorbtion.
References:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Pharmaceutical Research and Manufacturers of America (PhRMA). Pharmaceutical Industry Profile 2004
(Washington, DC: PhRMA, 2004). http://www.phrma.org/publications/publications/2004-03-31.937.pdf (FullText)
Berenson A., Pricey Drug Trials Turn Up Few New Blockbusters. New York Times, December 18, 2004
Sheehan P. The Quality Use of Medicines: Serving Health and Economic Objectives? CSES Working Paper
No. 21 October 2003 Victoria University (Melbourne). http://www.cfses.com/documents/wp21-mk.PDF (FullText)
Crowley P.J., and Martini L.G. Formulation design: new drugs from old (2004) Drug Discov.Today:
Therapeutic Strategies 1, 537–542
Коржавых Э.А., Румянцев А.С. Таблетки и их разновидности, Российские аптеки, 2003 г., №12.
Corrigan O.I. (1997) The biopharmaceutic drug classification and drugs administered in extended release (ER)
formulations. Adv. Exp. Med. Biol. 423, 111–128
Theeuwes F. Elementary osmotic pump. J. Pharm. Sci. 64, 1987–1991 (1975).
Theeuwes F. et al. Elementary osmotic pump for indomethacin. J. Pharm. Sci. 72, 253–258 (1983).
Anderson R. et al. Once-a-day controlled release versus immediate release oxybutynin chloride in the treatment
of urinary urge incontinence. J. Urol. 161, 1809–1812 (1999).
Versi, E., Appell, R., Mobley, D., Patton, W. and Saltzstein, D. Dry mouth with conventional and
controlledrelease oxybutynin in urinary incontinence. Obstet. Gynecol. 95, 718–721 (2000).
Columbo P. et al. Drug release modulation by physical restrictions of matrix swelling. Int. J. Pharm. 63, 43–48
(1990).
Conte U., Maggi L., Colombo P. and La Manna A. Multilayered hydrophilic matrices as constant release
devices. J. Control. Release 26, 39–47 (1993).
Conte U., Colombo P., Maggi L. and La Manna A. Compressed barrier layers for constant drug release in
swellable matrix tablets. STP Pharm. Sci. 4, 107–113 (1994).
Conte U. and Maggi L. Modulation of the dissolution profiles from Geomatrix multi-layer matrix tablets
containing drugs on different solubility. Biomaterials17, 889–896 (1996).
Biederman J. et al. Efficacy and safety of Ritalin LA, a new, once daily, extended-release dosage form of
methylphenidate, in children with attention deficit hyperactivity disorder. Paediatr Drugs. 5, 833–841 (2003).
Semenchuk M. R. Avinza Elan. Curr. Opin. Investig. Drugs. 3, 1369–1372 (2002).
Singh B.N. (1999) Effects of food on clinical pharmacokinetics. Clin.Pharmacokinet. 37, 213–255
Lin H.C. et al. (2003) Slowing of intestinal transit by fat or peptide YY depends on betaadrenergic pathway.
Am. J. Physiol. Gastrointest.Liver Physiol. 285, G1310–G1316
Davis S.S. Formulation strategies for absorbtion windows. Rewiew. Drug Discovery Today 2005, Vol.10, N 4
, pp. 249 - 257
Salama N.N. et al. (2004) The effect of DeltaG on the transport and oral absorption of macromolecules. J.
Pharm. Sci. 93, 1310–1319
Chourasia M. K. and Jain S. K. Design and development of multiparticulate system for targeted drug delivery
to colon. Drug Deliv. 11, 201–207 (2004).
Wilding I. and Prior D.V. (2003) Remote controlled release capsules in human drug absorption (HDA) studies.
Crit. Rev. Ther. Drug Carrier Syst. 20, 405–431
23. Ших Е.В. Взаимодействия компонентов витаминно-минеральных комплексов и рациональная
витаминотерапия. РМЖ, 2004, том 12, № 17.
24. Gatley M.S. To be taken as directed. J R Coll Gen Pract 1968; 16: 39-44.
25. Urquhart J. Controlled drug delivery: therapeutic and pharmacological aspects . Journal of Internal Medicine
2000; 248: 357-376.
26. Anonymous. Helping patients to make the best use of medicines. Drug Therap Bull 1991; 39: 1-2.
27. Pullar T., Kumar S., Tindall H., Feely M. Time to stop counting the tablets? Clin Pharmacol Ther 1989; 46:
163-8.
28. Rudd P., Byyny R.L., Zachary V. et al. The natural history of medication compliance in a drug trial: limitations
of pill counts. Clin Pharmacol Ther 1989; 46: 169-76.
29. Kruse W., Rampmaier J., Ullrich G., Weber E. Patterns of drug compliance with medication to be taken once
and twice daily assessed by continuous electronic monitoring in primary care. Int J Clin Pharmacol Ther 1994;
32: 453-7.
30. Rosen H., Abribat T. The rise and rise of drug delivery. Nat Rev Drug Discov. 2005 May;4(5):381-5.