Advanced and controlled drug delivery systems in clinical disease management
`
`• J.R.B.J . Brouwers
`
`In troduction
`In the last ten years many new advanced drug deliv(cid:173)
`ery systems have made the transition from the labora(cid:173)
`tory to clinical applications. In this article a review is
`given on advanced delivery systems that reached the
`phase of clinical application and which proved effec(cid:173)
`tive or have decreased toxicity compared with classi(cid:173)
`cal dosage forms. The headlines in the research field
`of advanced drug delivery are the development of:
`- Novel macromolecular and supra- molecular mate(cid:173)
`rials for drug delivery.
`e.g.: biogradable polymers, hydrogels, poly(cid:173)
`methylmetaacrylate, cyclodextrines.
`- Novel drug delivery systems:
`e.g.: liposomes, micellar systems, transdermal
`systems, improved systems for oral delivery,
`external- and implantable pumps.
`- New therapeutic approaches based on advanced
`drug delivery.
`e.g.: gene therapy, chemotherapy and infec(cid:173)
`tions, brain drug delivery, peptide and protein
`delivery coating on implantables [1 2).
`The goal of advanced drug delivery systems is to
`get the drug to the site of the target organ. This
`means a high concentration of the d rug in the tissue
`or at the receptor site with the lowest possible con(cid:173)
`centrations in other non-target organ systems to pre(cid:173)
`vent toxicity.
`In this review the advanced and controlled delivery
`systems which are practiced in the drug treatment are
`discussed.
`
`Ana tomic al and physiological constraints
`for drug delivery
`To deliver a drug to its site of action, physiological
`constraints have to be taken into account. In some
`representative examples constraints for drug delivery
`are shown.
`
`The gastrointestinal tract as important barrier for
`systemic drug delivery
`
`Example 1: Cefuroxim
`Cefuroxim is an anti-infective drug, with a broad
`spectrum against Gram (+) and Gram (-) bacteria.
`The main barrier for cefuroxim is the gastrointestinal
`tract. Thus we have to administer the drug by the
`parenteral route. Recently, a pro-drug of cefuroxim
`was introduced in clinical practice: cefuroxim-axetil.
`After oral administration cefuroxim-axetil is metabo(cid:173)
`lised (hydrolised) to the active compound cefuroxim
`in the mucous membrane of the gut and blood [3).
`Although the bioavailability is only 30-50%, the drug
`can be administered by the oral route in low to medi(cid:173)
`um grade infections of the urinary tract and lungs. In
`serious infections the blood levels are too low, and
`parenteral administration is obligatory.
`
`/RB/ Brouwers. Advanced and controlled drug delivery systems in
`clinical disease management
`Phorm World Sci 1996;1B(5): 153-162.
`01996 Kluwer Acodemtic Publishers. Prir(ed 111 the Netherlands.
`
`J.R.B.J. Brouwers. Professor of Clinical and Hospital
`Pharmacy. Groningen-Utrecht Institute for Drug Exploration
`(GUIDE), Division of Pharmacokinetics and Clinical
`Pharmacy, Department of Social Pharmacy and
`Pharmacoepidemiology, State University Groningen,
`Antonius Deusinglaan 2, 9713 AW Groningen, The
`Netherlands.
`
`Keywords
`Advanced drug deliveiy
`Controlled drug deliveiy
`Clinical practice
`Review
`
`Abstract
`Advanced and controlled drug delivery systems are
`important for clinical disease management. In this review the
`most important new systems which have reached clinical
`application are highlighted.
`Microbiologically controlled drug delivery is important for
`gastrointestinal diseases like ulcerative colitis and distally
`localized Crohn's disease. In cardiology the more classic
`controlled release systems have improved patient
`compliance and decreased side effects. In the treatment of
`intractable pain the spinal and transdermal route is well
`documented.
`In neurology the flattened peak-through levels of
`antiepileptic drugs and anti Parkinson's drugs represents a
`more predictable kinetic profile.
`Tracheal delivery of corticosteroids and
`sympaticomimetics in asthma and Chronic Obstructive
`Pulmonary Disease is fully accepted in clinical practice:
`delivery by this route results in better efficacy and a better
`safety profile .
`In gynaecology the delivery of pulsatile hormones (LHRH)
`is used for pregnancy induction, while transdermal
`oestrogens are promising in the prevention of osteoporosis.
`In surgical practice the use of antibiotic impregnated bone
`cement and antibiotic impregnated biodegradable collagens
`is well established.
`To prevent infections intravascular catheters coated with
`heparin or antibiotics are used.
`In ophthalmology the Ocuseit• systems provide a
`controlled release of different drugs in the eye.
`Most spectacular is the clinical introduction of the first
`liposomal drugs: amfotericine Band daunorubicine.
`Liposomal formulations of these drugs have enhanced
`activity and decreased toxicity compared to conventional
`formulations.
`
`Accepted May 1996.
`
`.. ;;
`i
`153
`Mylan Exhibit 1026
`
`~
`
`

`
`Example 2: Cyclosporin A
`Cyclosporin A is a water insoluble cyclic decapeptide.
`It is a powerful immunosuppressant drug and a cor(cid:173)
`nerstone in immunosuppression protocols for organ
`transplantation. Cyclosporin A has a highly variable
`bioavailability within the range of 10-60% after oral
`dosing.
`Gastrointestinal absorption was shown to be limit(cid:173)
`ed by its poor aqueous solubility, by a slow adsorption
`rate driven by passive diffusion, and by a narrow
`absorption window. Since the dru-g is potentially
`nephrotoxic, Therapeutic Drug Monitoring is manda(cid:173)
`tory to maintain its blood level in the therapeutic
`range. Patients have to take the drug on an outpa(cid:173)
`tient basis for months, so it is unrealistic to administer
`the drug by the {more predictable) parenteral route.
`A new dosage form of cyclosporin A (Neoral®) was
`recently developed which fulfills the criteria of a more
`stable and predictable bioavailability [4].
`By using the concept of 'micro-emulsion' based on
`lipophilic sol(cid:173)
`a mixture of a hydrophilic solvent, a
`vent, and a surfactant together with the active ingre(cid:173)
`dients a thermodynamically stable and self-emulsify(cid:173)
`ing formulation is now available.
`By diluting the micro-emulsion in aqueous fluids,
`micellar droplets are formed in situ (stomach, small
`bowel) in a reproducible size of about 30 nm. These
`micelles are relatively stable in the b io-emulsifiers in
`the gut such as bile acid. This may be of benefit in
`patients who show poor absorption of cyclosporin A
`from the standard oral preparation, e.g. liver trans(cid:173)
`plant recipients w ith biliary diversion or cholestasis.
`[5]
`
`enter the brain in the absence of a delivery system.
`Because designing drugs to cross the blood-brain bar(cid:173)
`rier offers so many difficulties, it seems the fastest way
`to deliver the potential drug behind the blood barrier
`instead of crossing it.
`
`Example 3: Baclofen in spasticity
`In serious cerebral spasticity the administration of
`high dose oral baclofen is limited by its side effects:
`intestinal
`sedation, dizziness, hypersalivation and
`pseudo-obstruction. In order to prevent side effects
`and to permit a fine tuning of dosage, continuous
`intrathecal (low dose) baclofen infusion is an exciting
`new option.
`The baclofen dosages can be titrated for the
`desired clinical response. This is extremely important
`in patients who need some muscle tone to stand and
`to remain ambulant. The Synchro Med Implantable
`Infusion System (Medtronic Inc, Minneapolis, Minn)
`permits delivery of baclofen by a programmable
`pump and it appears to be reliable for site-specific
`drug delivery into CSF. The infusion pump measures
`7.5x2.8 cm (formed like a ice-hockey puck) and con(cid:173)
`tains a 18 ml drug re.servoir which can be filled by
`percutaneous punction through a septum. Dosage
`adljustments can be made via an external computer
`and transmitted to the pump by a hand held radio
`frequent box.
`The implanted pump gives the patients the free(cid:173)
`dom and flexibility of a more acceptable lifestyle with
`an enhanced quality of life (7 8].
`
`Vascularization or ischemia in the target tissue as barri
`er
`
`The blood-brain barrier as the main barrier [ 6]
`
`Example 4: Unresectable liver metastasis
`The blood-brain barrier is a bottle neck in developing Liver metastases are observed at diagnosis of primary
`brain-targeted drugs for the treatment of human cen- colorectal cancer in 2.5-30% of patients, and up to
`tral nervous system (CNS) disorders. Only lipid and sixty percent of patients develop liver metastasis dur(cid:173)
`ing the course of their disease. Perioperative intrapor-
`small molecules are able to cross the barrier and to
`
`Tal»le l Site of 5-ASA release from various dosage forms
`
`Generic
`
`Trade name
`
`Formulation
`
`pH-dependent
`
`Site of
`release
`
`Mesalazine
`
`Pentasae
`
`Mesalazine
`
`Salofalk9
`
`Coated microgranules
`compressed in tablet
`with ethylcellulose
`coating
`
`Eudragit L-100
`coated
`
`No
`
`pH>6
`
`Mesalazine
`
`Asacol®
`
`Eudragit S coated
`
`pH>7
`
`Sulphasalazine
`
`Salazopyrinee Dragee
`taste coating
`
`Olsalazine
`
`Dipentum9
`
`Gelatine capsule
`
`Balsalazine
`
`Cofazid~
`
`Tablet
`
`No
`
`No
`
`No
`
`Duodenum
`Jejunum
`Ileum
`Colon
`
`jejunum
`Ileum
`Colon
`
`Ileum
`Colon
`
`Colon
`
`Colon
`
`Colon
`
`:;,
`
`t • • " ~
`i!:
`'l> g
`
`~
`
`~ i ..
`
`('
`
`~
`
`~
`"'
`
`154
`
`

`
`(jtf'Jeric ~
`
`>•.<IC:* ~dciss
`
`T~
`
`AdalatOros
`
`111'4iem CR/Sorazem
`lsOptln SR
`
`L..oml11SR
`selokeen zoc
`lnderal R$rd
`
`Catapressan Pcriogetten
`
`Catapresan dermal patch
`Nitfo..dur ~ pate!\
`ltansiderm patch
`Cedocard Retard nitrates
`MOncicebocard ~ .
`PtomOc..wd Durette
`
`Nifedipine
`
`Dtltlamn
`Verapamil
`
`lsradipine
`
`Metoprolol
`Propranolol
`Clonidine
`
`Nitrogtycerine
`Ni~erine
`
`lsosOmideniononltrte
`lsosofbldemononte.
`
`Calcium cNnnef
`8lodcing agent
`
`H
`
`"
`,,
`B-bloding agent
`
`Antihypertensive
`(undassified}
`
`Nitrates
`
`Nitrates
`
`lsosorbidedinitrate
`
`Nitrates
`
`Nitrates
`
`MtHntiithmic drug
`
`Procalnamtde·~ ~
`IUtmoforine RtlWd
`
`Disopyramide
`
`tal cytotoxic agents as well as hepatic arterial hepatic
`infusions of cytotoxic agents have some additional
`therapeutic value (9 10].
`Because of necrosis in the tumor or metastasis it
`may be difficult to achieve high cytotoxic drug levels
`in the target tissue. Furthermore, thP (re)vaS<ulari~­
`tion in or around the tumor metastasis may be
`another contributing factor in the relative inefficacy of
`cytotoxic drugs in hepatic metastasis colorectal can(cid:173)
`cer. Thus, to enhance the efficacy, site-specific deliv(cid:173)
`ery of cytotoxic drugs (5-fluorouracil, floxuridine) via
`the hepatic arterial system has been proven to be well
`tolerated, but moderately effective [11 12].
`
`Chronobiological pattern as physiological barrier.
`
`E.xample 5: Luteinising hormone-releasing hor(cid:173)
`mone (LHRH) in ovulation induction
`Gonadorelin antagonists have found a place in the
`treatment of a variety of conditions requiring suppres(cid:173)
`sion of the pituitary gonadal axis. Gonadorelin ago(cid:173)
`nist preparations are used for central precocious
`puberty (leuprolide), in vitro fertilization (buserelin,
`nafarelin), endometriosis (e.g. buserelin, goserelin,
`leuprolide) and the long term palliation of prostate
`cancer (buserelin, goserelin, leuprolide) or breast
`cancer (goserelin). Intranasal delivery, standard injec(cid:173)
`tions and depot injections are used depending on the
`different indications. In the treatment of infertility,
`gonadorelin agonists are increasingly used in assisted
`reproductive program in combination with pulsatile
`gonadorelin (LHRH). LHRH can restore a normal pitui(cid:173)
`tary function. Surprisingly, the normal function can
`only be obtained bij mimicking the chronobiological
`clock. Thus, with the use of a special pulsatile (exter(cid:173)
`nal) pump, a small bolus is administered every 90-120
`
`min to mimic the normal physiological pattern of the
`hormone release. Fertility induction by LHRH pulatile
`therapy is safer and more effective than gonadotro(cid:173)
`phin therapy (13].
`The examples as presented above show us that bar(cid:173)
`riers or biological issues may be taken into account
`depending on the therapeutic options we want to
`reach. The dosage forms with advanced or controlled
`drug delivery will be highlighted now in more detail.
`
`Gastroenterology
`5-Aminosalicylate (5-ASA, mesalazine)
`
`In gastrointestinal disease site-specific delivery of
`drugs is sometimes warranted. Normally we want the
`drug to be absorbed rapidly in the small intestine but
`in some complaints the large bowel is the target tis(cid:173)
`sue. Microbiologically controlled drug delivery to the
`colon has been used for more than 35 years (14].
`Sulphasalazine is degraded by bacterial enzymes in
`the colon into the active part of the drug mesalazine
`(5-ASA) and sulphapyridine.
`In the small intestine there is a low bacterial count
`while in the colon the bacterial count is high, so most
`of the free 5-ASA is split off from sulphasalazine and
`delivered in the colon.
`Sulphapyridine is not a therapeutically active deg(cid:173)
`radation product, while it causes most of the side
`effects of the drug. Thus a second generation of pro(cid:173)
`drugs for colon delivery of 5-ASA was developed. Two
`of them reached clinical application: olsalazine and
`balsalazine. Olsalazine seems the most promising
`option; it utilizes an azo bond to link two molE>cules of
`5-ASA and this results in a predictable, 5-ASA pharma(cid:173)
`cokinetic profile similar to half the dose of sulphasala-
`
`155
`
`"'
`j
`
`

`
`Table 3 Transdtrmol drug dtlivtry systems (pat~)
`
`Indication
`
`Clonidine
`Fent.any!
`Nicotine
`
`Nitroglycerin
`Estrogen
`Comb. Estrogen/ progestagen
`Pilocarpine
`
`Relevance
`
`Oinica/
`Literature
`
`Hypertension
`Pain
`Smoking cessation
`Ulcerative Colitis
`Angina pectoris
`Estrogen substitute
`Osteoporosis
`Motion sickness
`
`±
`+
`
`+
`+/(cid:173)
`+/(cid:173)
`+/·
`+/++
`
`[90]
`
`++ Clinically very relevant, no other treatment options available.
`+ Clinically relevant, w hen other treatment options are sometimes not applicable (nausea, vomiting, GI,
`disturbed drug absorptions) [86].
`+/- Clinically attractive, but other treatment options are available.
`Doubt about the clinical effectiveness.
`
`zine [15). Controlled drug delivery systems with
`mesalazine itself is another option to get a high con(cid:173)
`centration of 5-ASA into the colon [16). Two thera(cid:173)
`peutic systems are available:
`individually coated
`microgranules compressed into tablets with an ethyl(cid:173)
`cellulose coating (e.g. Pentasa®} and a pH dependent
`Eudragit coating (e.g. Salofalk®, Asacol®). Although
`differences in the site of release of 5-ASA from differ(cid:173)
`ent dosage forms can be expected (Tabet 1) the effi(cid:173)
`cacy of all the preparations is comparable (17]. pH(cid:173)
`dependent delivery systems can be prone to dose
`dumping when combined with antacids. Mesalazine
`released from pH-dependent delivery systems have
`been related more often with nephrotoxicity than
`microbiologically controlled release systems [18 19).
`
`Laxatives
`
`Another example of bacterial cleavage is the laxative
`action by anthracene derivatives.
`Senna preparations contain anthracene derivatives
`as glycosides. Hydrolization by the colon flora can
`release the active anthraquinones [14 ].
`The synthetic laxative sodiumpicosulfate is degrad(cid:173)
`ed by the arylsulfatase activity in the colon lumen to
`the 'active' compound 3 (p-hydroxyphenyl) pyrid-2-
`yl-methane.
`The clinical value of the cleavage in the colon is
`that the drug acts than on the site of action and does
`not give local irritation in the stomach or small intes(cid:173)
`tine.
`
`Nicotine transdermal delivery
`
`In trials nicotine has been shown to be moderately
`effective in colitis. The transdermal route seems an
`option to release the relapse of colitis in patients who
`stopped smoking.
`Futhermore it seems effective in steroid resistant
`colitis(Table 3).
`
`Steroids
`
`"' j
`
`156
`
`In inflammatory bowel disease {IBD) the clinical effect
`of 5-ASA preparation is sometimes too weak, especial-
`
`ly in Crohn's disease. Oral prednisolon has been for
`many years a cornerstone in the treatment of IBD. If
`the inflammation area is localized in the descendent
`colon, prednisolone or beclomethasone enemas are
`used. But the beneficial effects of classic glucocorti(cid:173)
`costeroids are offset by troublesome and sometimes
`irreversible systemic side effects [20).
`Budenoside seems to be the most promising of the
`new fluorinated glucocorticosteroids. A refined slow
`release delivery system has been devised by Astra
`Draco AB Sweden, using 1 mm sized enteric coated
`(Eudragit L) pellets with rate-limiting polymer con(cid:173)
`taining the active drug. The time and pH-dependent
`delivery system ensures a release of approximately
`70% of the given drug in the distal ileum and cecum.
`Another way to deliver glucocorticosteroids to the site
`of inflammation in the gut is the use of a prodrug.
`Budenoside-B-0-glucuronide is not absorbed in the
`intestine but hydrolyzed by the colonic bacterial and
`mucosal B-glucuronidase. When entering the colon,
`free budenoside is delivered. Budenoside absorption
`is very low and when it is absorbed it is rapidly metab(cid:173)
`olized in the liver to nearly inactive metabolites which
`have only <1 % of the potency of the parent drug.
`Thus, systemic side effects can be prevented even
`when high dosages of budenoside are warranted
`[21 ]. So budenoside-~-D-glucoronide seems to be the
`drug of choice for the future in this clinical condition.
`Other therapeutic options for advanced drug deliv(cid:173)
`ery in gastroenterology are: new pancreatic enzyme
`preparations. These preparations are of clinical value
`because they are not prone to degradation by gastric
`juice.
`Selective targetting of antivirals in the liver for
`patients with chronic hepatitis is an experimental
`option [22J.
`
`Cardiology [23)
`Traditionally, buccal nitroglycerin is a well established
`dosage form in the treatment of episodic angina pec(cid:173)
`toris. However, inconvenience of the buccal dosage
`forms e.g. irritation, interference with eating and talk(cid:173)
`ing, has stimulated research to other forms of delivery
`and today three other dosage forms of nitroglycerin
`
`

`
`are available: a dermal preparation, a transdermal
`delivery system (patch) and a spray for rapid onset of
`action.
`Most of the newer cardiac formulations are sus(cid:173)
`tained release oral formulations. This permits a lower
`dose frequency (which promotes compliance), a
`lower incidence of side effects and an enhanced ther(cid:173)
`apeutic profile. Most advanced dosage forms are used
`in anti-hypertensive drugs and anli-anginal drugs.
`Recently, an oral novel delivery system with release of
`verapamil mimicking a physiological pattern was eval(cid:173)
`uated. It was shown that the novel delivery system of
`verapamil administered nocturnally produced chang(cid:173)
`es in blood pressure following the circadian variability
`of blood pressure (24). Pharmacokinetic analysis of a
`new oral sustained release preparation of dilthiazem
`showed that once daily treatment may be equivalent
`to older slow release preparations for twice daily
`treatment (25).
`Another goal of antihypertensive therapy is to get
`the blood pressure peak and through levels within
`certain limits. The through-peak ratio should be
`<50% (26).
`The use of controlled release dosage forms can ful(cid:173)
`fill the criteria. In Table 2 some of the controlled
`release preparations useful in cardiovascular disease
`are presented.
`Most important is the fact that the controlled
`release preparation can be administered once or
`twice a day which is important for patient compliance
`for this type of drugs (27).
`
`Pain treatment
`
`Opioids
`
`The introduction of controlled release dosage forms
`of morphine permits a round-the-clock effective treat(cid:173)
`ment of cancer pain. Years ago it was a myth that
`morphine could not be administered orally.
`lntractcible pain can be treated today with controlled
`release morphine and this is the mainstay of pain
`treatment In cancer pain and, sometimes, in non(cid:173)
`malignant pain (28). The biological availability of the
`different controlled release morphine preparation
`(M S-Contin9 , Noceptin9 , Kapanof!') is comparable,
`so the cheapest is the best.
`Another new exciting area is the delivery of opioid
`by the epidural or intrathecal route[26). This permits
`lower dosage of morphine and fewer side effects.
`Other drugs used by the spinal route are fentanyl,
`sufentanil and buprenorphine. A tramdennal thera(cid:173)
`peutic system of fentanyl has been recently devel(cid:173)
`oped (see section Transdermal Drug Delivery). More
`experimental are morphine controlled release prepar(cid:173)
`ations from microspheres as a site-specific delivery
`form (30), and the intranasal administration of fenta(cid:173)
`nyl and alfentanyl for post-operative pain relief (31 ).
`Another new and exciting method is the use of a
`metered dose breath-actuated inhaler with fentanyl
`which was introduced to reduce post-operative pain
`(32).
`The rectill administration of morphine is poorly
`documented and that is probably the reason why its
`clinical use so far has not yet been established. There
`are preliminary notes that rectal administration of
`
`MS-Cantin in tablets is useful (33). Concerning the
`predictability of the absorption profile methadone
`seems more promising (34). Although there has been
`some research on advanced rectal drug delivery of
`morphine, it has not reached clinical application up
`till now [35 36).
`Oral transmucosal fentanyl citrate seems valuable
`as premedication to prevent pain in children under(cid:173)
`going small surgical interventions and for dermato(cid:173)
`logic painful! procedures (37 38).
`
`Local anesthetics
`
`The addition of epinephrine to local anesthetic solu(cid:173)
`tions delays absorption and prolongs the duration of
`action. But epinephrine may be contra-indicated in
`some patients. Thus, local anesthetics were recently
`incorporated into liposomes in order to release drug
`absorption rate. Most studies uptill now have been
`performed with liposomal bupivacaine. This formula(cid:173)
`tion has a long duration of action but whether these
`preparations are less neurotoxic has still to be shown
`and more systematic studies are required before clini(cid:173)
`cal introduction (39).
`
`NSA/Ds
`
`Controlled release formulations of non-steroidal anti(cid:173)
`inflammatory drugs (NSAIDs) were developed to flat(cid:173)
`ten the plasma concentration curve, minimizing circa(cid:173)
`dian variation, preventing gastro-intestinal toxicity
`and, last but not least, rendering drug administration
`more convenient for the patients by reducing the
`number of daily doses (40].
`Enteric-coated preparations control the onset of
`absorption. In most cases the protective acid-resistant
`coating delays the desintegration and dissolution of
`the tablet until it reaches the duodenum. But, unfor(cid:173)
`tunately, the prevention of local irritation does not
`seem to contribute importantly in the prevention of
`gastric ulceration and gastro-intestinal bleeding.
`The inclu~ion of piroxicam in a B-cyclodextrine
`(8rexine®) matrix seems an attractive feature in pre(cid:173)
`venting gastric irritation. However, in clinical studies it
`was shown that systemic effects of the NSAIDs are the
`most
`important markers for gastrointestinal side
`effects (41 42).
`An osmotic pump system with indomethacin was
`briefly marketed in the United Kingdom and The
`Netherlands in 1983. The formulation was technically
`elegant and allowed the release of the drug with
`remarkable constancy and predictability. But, shortly
`after maketing, however, cm unusually high number
`of spontaneous reports of serious gastrointestinal side
`effects led to withdrawal from clinical use. The con(cid:173)
`centrated local corrosive action together with an
`enhanced enterohepatic
`recirculation
`(through
`increased systemic bio-availability) of indomethacin
`were probably responsible for the higher gastrointes(cid:173)
`tinal toxicity.
`Multi-unit controlled release systems are frequently
`used for NSAIDs. They exist in several shapes, from
`capsules filled with several hundred pellets consisting
`of drug absorbed on an inert core and coated with an
`acid resistant layer to solid forms that disintegrate in
`the intestine to several individually coated units. The
`most common presentations of the pellet-type are:
`
`'.;! l f:
`/)I r
`f .. i
`
`~
`
`j
`
`157
`
`

`
`lndocid-R (capsules with slow-release i'ndomethacin)
`and Orudis retard (tablets) and Oscoirel with slow(cid:173)
`release ketoprofen.
`Thus, the most important factor for controlled
`release in NSAIDs is the 'convenience' and 'easier to
`remember' to prevent multiple daily dose. The pre(cid:173)
`vention of gastrointestinal side effects by controlled
`release NSAIDs is a false claim.
`
`cation for asthma was g iven by the oral route. Now
`the use of the metered dose inhalation system to get
`the drug to the site of action (the lungs) is clinically
`well established for corticosteroids, ~-agonists and
`ipratropium. The use of inhaled drugs seems a very
`effective, relatively safe, method for all patients with
`asthma or COPD.
`
`Neurology and p sychiatry
`In neurology, epilepsy and Parkinson's disease are
`modalities for controlled release dosage forms. For
`most of the anti-epileptic drugs there is a clear rela(cid:173)
`tion between blood levels and clinical effect and tox(cid:173)
`icity. A too low blood level before the next dose is
`associated with seizures, and the use of controlled
`drug delivery may prevent this. At least two formula(cid:173)
`tions with controlled drug delivery are now marketed:
`valproic acid (Depakine Chrono®) and carbamaze(cid:173)
`pine (Tegretol CR). Most important is the prevention
`of (very) low blood levels of the anti-epileptic drug in
`the morning (dip), thus better preventing ('early
`morning') insults.
`Levodopa remains central to drug treatment of
`Parkinson's disease. It is given in combination w ith
`peripheral dopa-decarboxylase inhibitor such as car(cid:173)
`bidopa (in co-careldopa: Sinemet® ) or benserazide
`(in co-beneldopa: Madopar®). To minimize unwanted
`effects such as nausea, vomiting and postural hypo(cid:173)
`tension the drug is started at a low dose of about 1 25-
`500 mg daily in divided doses with a conventional
`preparation. Modified-release levodopa preparations
`slow the absorption of levodopa and produce pro(cid:173)
`longed and steady-state plasma concentration of the
`drug. Modified release preparations of both co-carel(cid:173)
`dopa (Sinemet CR) and co-beneldopa: (Madopar
`HBS) are available.
`These formulations reduce 'wearing off time' and
`for this reason many patients prefer them to standard
`preparation. For clinical reasons - when symptoms
`become more severe - a combined approach w ith
`both standard and modified release preparation is
`used. To prevent nocturnal akinesia, slow release
`properties may also be an advantage (431.
`The usefulness of controlled drug delivery for anti(cid:173)
`depressant drugs is. of minor importance. Lithium and
`some tricyclic anti-depressant drug are available in a
`controlled release form. For lithium, a drug with a
`long half life, the controlled release form has a reliable
`taste compared to t he plain lithium carbonate tablets.
`For antidepressant drugs the controlled release princi(cid:173)
`is of minor importance (relevance: only to
`ple
`improve patient compliance).
`Depot antipsychotic drugs are very useful in non(cid:173)
`compliant patients with schizophrenia. Patients show
`fewer relapses when continuous treatment is used.
`One of the problems is the patient selection to estab(cid:173)
`lish the need for prophylactic anti-psychotics (44J.
`
`Asthma and COPD
`The use of controlled release preparations for theo(cid:173)
`phyline is well established because they permit once
`or twice daily dosages. The flattened absorption pro(cid:173)
`file may prevent sid e effects which are associated with
`peak levels. More than ten years ago nearly all medi-
`
`Gynaecology and obstetrics
`The use of Intra Uterine Devices for birth control is
`well established. The release of copper for the
`Copper-T IUD is very effective for birth control (45].
`IUD release of prostagens has been abandoned years
`ago.
`Local intravaginal application of prostaglandin gel
`is an effective method to prepare the cervix for deliv(cid:173)
`ery.
`In the prevention of osteoporosis in post-menopau(cid:173)
`sal women, the supplementation of estrogen seems
`an effective strategy. From a survey in the USA it was
`shown that 50 percent of women discontinue an oral
`oestrogen therapy. Long-term treatment with low
`dose estradiol implants seems to preserve both com(cid:173)
`pact and cancellous bone. The bone mineral density
`in women using implants is 20-25 percent higher
`than in women in the age-matched control groups
`[46].
`Transdermal drug delivery of estrogens (with or
`without progesterone) is another option for estrogen
`substitution. There are no comparative studies to
`show whether transdermal drug delivery may give
`more compliance compared to an oral dosage form.
`
`Surgery
`The efficacy of prophylactic antibiotics for orthopedic
`implant surgery is well established. Failure to use anti(cid:173)
`biotics has been estimated to result in a seven-fold
`increase in the rate of infection. One of the methods
`to reduce infection rate is the use of antibiotic
`impregnated cements
`(47]. Gentamicin-loaded
`cement (mostly polymethylmetha-acrylate cement)
`yielded high levels of the antibiotic in wound drain(cid:173)
`age fluid for several days after operation.
`Antibiotics which are used in bone cement in clini(cid:173)
`cal p ractice are gentamicin (Palacos®), tobramycine,
`vancomycine, ciprofloxacin and colistin with eryth(cid:173)
`romycine (Simplex®) (48 49].
`Recently, biodegradable bone cement for treat(cid:173)
`ment and prophylaxis of osteomyelitis was intro(cid:173)
`duced [50J. Biodegradable collagen impregnated
`with gentamicin (Garacci®) is used in the treatment
`of osteomyelitis and as an adjuvant in injected total
`hip replacements and in groin wound infections (51
`52].
`Infection is the most dreaded complication of vas(cid:173)
`cular reconstructive surgery, especially when the
`aorta is involved. Thus, in vascular surgery prosthetic
`graft infection should be prevented at any price (53].
`The development of infection-resistant vascular pros(cid:173)
`theses may be very useful to reduce the morbidity
`and mortality for excision or extra anatomic recon(cid:173)
`struction of infected prostheses.
`Antibiotic-loaded gelatin or collagen sealed Dacron
`or Teflon grafts are used
`in clinical practice.
`Rifampicin-loaded gelatin-sealed Dacron grafts seems
`
`~
`
`&
`
`158
`
`

`
`the most reliable for clinical practice [54 55].
`Coating of external vascular catheters is used to
`prevent bacterial adhesion and colonization of bacte(cid:173)
`riae [56].
`The surface of a cannula after insertion intravascu(cid:173)
`larly is rapidly covered by plasma and tissue proteins.
`Platelets and leukocytes adhere to the surface thus
`promoting a fibrin network covering the catheter.
`Micro-organisms can be mechanically trapped in the
`fibrin and are the cause of infections, flebitis or line
`sepsis.
`To prevent adhesion of microbes, heparinization of
`catheters has been shown to be very effective. An
`infection reduction of more than 50% seems possible
`with the stable heparin coating (Carmeda Bioactiv
`surface= CBAS) of intravascular catheters [57).
`The antiseptic drug benzalkoniumchloride has
`been tested (in vitro) on a hydrophilic-coated (hydro(cid:173)
`cath) catheter. The adherence of strains of
`Staphylococcus epidermidis was significantly reduced
`compared to standard external polyurethane catheter
`[58].
`Although coating of the catheters with antibiotics
`(rifampicin plus minocyclin) seems to prevent colon(cid:173)
`ization of slime-producing staphylococci, non-antibi(cid:173)
`otic coatings seem more attractive in terms of induc(cid:173)
`tion of avoiding antibiotic resistance [59].
`
`effectiveness and toxicity profile has only been sub(cid:173)
`ject in uncontrolled trials [65). A cumulative dose of
`approximately 4 g (2.8 mg/kg) will cost at least SUS
`12,500 [66).
`Other potential applications of liposomes are the
`inclusion of gentamicin and foscarnet to prevent tox(cid:173)
`icity and enhance the effect. Up