!!!!
`
`Exhibit 1026
`Brouwers, J.R.B.J. “Advanced and
`controlled drug delivery systems in clinical
`disease management,” Pharmacy World &
`Science: (1996) 18(5), 153-162
`(“Brouwers”)
`
`

`
`
`
`%1!11 84184 84184
`
`i 84
`
`~iii!~
`
`
`
`i ii!iiii!!ii!!i!i
`
`Advanced and controlled drug delivery systems in clinical disease management
`
` 9 J.R.B.J. Brouwers
`
`Introduction
`In the last ten years many new advanced drug deliv-
`ery systems have made the transition from the labora-
`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-
`tive or have decreased toxicity compared with classi-
`cal dosage forms. The headlines in the research field
`of advanced drug delivery are the development of:
`- Novel macromolecular and supra- molecular mate-
`rials for drug delivery.
`e.g.: biogradable polymers, hydrogels, poly-
`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-
`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 drug in the tissue
`or at the receptor site with the lowest possible con-
`centrations in other non-target organ systems to pre-
`vent toxicity.
`In this review the advanced and controlled delivery
`systems which are practiced in the drug treatment are
`discussed.
`
`tract as
`
`important barrier
`
`Anatomical 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
`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-
`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-
`um grade infections of the urinary tract and lungs. In
`serious infections the blood levels are too low, and
`parenteral administration is obligatory.
`
`for
`
`153
`
`

`
`A
`2: Cyclosporin
`Example
`cyclic decapeptide.
`insoluble
`Cyclosporin
`A is a water
`drug and a cor-
`It is a powerful
`immunosuppressant
`protocols
`for organ
`nerstone
`in immunosuppression
`A has a highly
`variable
`transplantation.
`Cyclosporin
`bioavailability
`within
`the
`range of lo-60%
`after oral
`dosing.
`to be limit-
`was shown
`absorption
`Gastrointestinal
`ed by its poor aqueous
`solubility,
`by a slow adsorption
`rate driven
`by passive diffusion,
`and
`by a narrow
`absorption
`window.
`Since
`the
`drug
`is potentially
`nephrotoxic,
`Therapeutic
`Drug Monitoring
`is manda-
`tory
`to maintain
`its blood
`level
`in
`the
`therapeutic
`range. Patients have
`to
`take
`the drug on an outpa-
`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].
`based on
`By using
`the concept
`of ‘micro-emulsion’
`a mixture
`of a hydrophilic
`solvent,
`a
`lipophilic
`sol-
`vent, and a surfactant
`together with
`the active
`ingre-
`dients a thermodynamically
`stable and self-emulsify-
`ing formulation
`is now available.
`fluids,
`in aqueous
`By diluting
`the micro-emulsion
`small
`micellar
`droplets
`are
`formed
`in situ
`(stomach,
`bowel)
`in a reproducible
`size of about
`30 nm. These
`micelles are relatively
`stable
`in
`the bio-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-
`plant
`recipients with
`biliary
`diversion
`or cholestasis.
`[51
`
`The blood-brain
`
`barrier as the main barrier
`
`[6]
`
`in developing
`is a bottle neck
`barrier
`The blood-brain
`of human
`cen-
`drugs
`for the treatment
`brain-targeted
`system
`(CNS) disorders. Only
`lipid and
`tral nervous
`small molecules
`are able
`to cross
`the barrier
`and
`to
`
`system.
`of a delivery
`in the absence
`the brain
`enter
`drugs
`to cross the blood-brain
`bar-
`Because designing
`rier offers so many difficulties,
`it seems the
`fastest way
`to deliver
`the potential
`drug behind
`the blood barrier
`instead of crossing
`it.
`
`in spasticity
`3: Baclofen
`Example
`of
`spasticity
`the administration
`cerebral
`In serious
`high dose oral baclofen
`is limited
`by
`its side effects:
`sedation,
`dizziness,
`hypersalivation
`and
`intestinal
`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
`for
`titrated
`be
`can
`dosages
`The
`baclofen
`important
`response. This
`is extremely
`desired
`clinical
`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-
`tains a 18 ml drug
`reservoir which
`can be
`filled by
`percutaneous
`punction
`through
`a septum.
`Dosage
`adjustments
`can be made
`via an external
`computer
`and
`transmitted
`to
`the pump
`by a hand held
`radio
`frequent
`box.
`free-
`the
`the patients
`gives
`pump
`The
`implanted
`of a more acceptable
`lifestyle with
`dom and
`flexibility
`an enhanced
`quality of life [7 81.
`
`Vascularization
`er
`
`or ischemia
`
`in the target
`
`tissue as barri
`
`liver metastasis
`4: Unresectable
`Example
`of primary
`Liver metastases are observed
`at diagnosis
`and up
`to
`colorectal
`cancer
`in 2530%
`of patients,
`sixty percent
`of patients develop
`liver metastasis dur-
`ing
`the course of their disease. Perioperative
`intrapor-
`
`Table 1 Site of 5.ASA release ibn various dosage forms
`
`Generic
`
`Trade name
`
`formulation
`
`p/+-dependent
`
`Mesalazine
`
`Pentasa@
`
`Mesalazine
`
`Salofalk@
`
`Coated microgranules
`compressed
`in tablet
`with ethylcellulose
`coating
`
`Eudragit
`coated
`
`L-l 00
`
`Me&a&e
`
`ASXOP
`
`Eudragit S coated
`
`Sulphasalazine
`
`Salazopyrine@
`
`Dragee
`taste coating
`
`Olsalazine
`
`Balsalazine
`
`Dipentum”
`
`Celatine
`
`capsule
`
`CofazidC
`
`Tablet
`
`No
`
`pH>6
`
`pH>7
`
`No
`
`No
`
`No
`
`Site of
`release
`
`Duodenum
`Jejunum
`Ileum
`Colon
`
`Jejunum
`ileum
`Colon
`
`Ileum
`Colon
`
`Colon
`
`Colon
`
`Colon
`
`

`
`Nlldiipine
`
`5ilkzem
`VW+lpamii
`isradipine
`
`Metopmiol
`Pfopranolol
`Clonidine
`
`Nllogfyreime
`Ni*ceririe
`
`fsos&%ideniononRrate
`bsofbidemononitrate.
`Prwin$r*
`Dbq&mide
`
`Cakium
`B-
`
`f
`,,
`n
`n
`C-blocking
`
`channel
`agent
`
`agent
`
`Antihypertensive
`(unclassified)
`
`Nitrates
`Nitrates
`
`lsosorbidedinitrate
`N#rates
`Nitrates
`Anti-arrhithmic
`
`drug
`
`”
`
`agents as well as hepatic arterial hepatic
`tal cytotoxic
`infusions
`of cytotoxic
`agents
`have some additional
`therapeutic
`value
`[9
`lo].
`it
`or metastasis
`tumor
`the
`Because of necrosis
`in
`may be difficult
`to achieve high cytotoxic
`drug
`levels
`in the
`target
`tissue. Furthermore,
`the
`(re)vascularisa-
`tion
`in or around
`the
`tumor metastasis may be
`another
`contributing
`factor
`in the relative
`inefficacy of
`cytotoxic
`drugs
`in hepatic metastasis
`colorectal
`can-
`cer. Thus,
`to enhance
`the efficacy, site-specific
`deliv-
`ery of cytotoxic
`drugs
`(Sfluorouracil,
`floxuridine)
`via
`the hepatic
`arterial system has been proven
`to be well
`tolerated,
`but moderately
`effective
`[l 1 121.
`
`Chronobiological
`
`pattern as physiological
`
`barrier.
`
`hor-
`
`hormone-releasing
`5: Luteinising
`Example
`induction
`mone
`(LHRH)
`in ovulation
`the
`in
`a place
`have
`found
`Conadorelin
`antagonists
`treatment
`of a variety of conditions
`requiring
`suppres-
`sion of the pituitary
`gonadal
`axis. Conadorelin
`ago-
`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).
`lntranasal
`delivery,
`standard
`injec-
`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-
`tary
`function.
`Surprisingly,
`the normal
`function
`can
`only be obtained
`bij mimicking
`the chronobiological
`clock. Thus, with
`the use of a special pulsatile
`(exter-
`nal) pump, a small bolus
`is administered
`every 90-l 20
`
`of the
`pattern
`by LHRH pulatile
`than gonadotro-
`
`physiological
`the normal
`to mimic
`min
`induction
`hormone
`release. Fertility
`therapy
`is safer and more effective
`phin
`therapy
`[13].
`above show us that bar-
`The examples as presented
`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
`
`(S-ASA, mesalazine)
`
`of
`delivery
`site-specific
`disease
`In gastrointestinal
`the
`Normally we want
`drugs
`is sometimes warranted.
`but
`in the small
`intestine
`drug
`to be absorbed
`rapidly
`tis-
`in some complaints
`the
`large bowel
`is the
`target
`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
`(5ASA)
`and sulphapyridine.
`count
`is a low bacterial
`In the small
`intestine
`there
`count
`is high, so most
`while
`in the colon
`the bacterial
`of the
`free 5ASA
`is split off from sulphasalazine
`and
`delivered
`in the colon.
`active deg-
`Sulphapyridine
`is not a therapeutically
`radation
`product,
`while
`it causes most of
`the side
`effects of the drug. Thus a second generation
`of pro-
`drugs
`for colon delivery of S-ASA was developed.
`Two
`of
`them
`reached
`clinical
`application:
`olsalazine
`and
`balsalazine.
`Olsalazine
`seems
`the most
`promising
`of
`option;
`it utilizes an azo bond
`to link two molecules
`S-ASA and
`this results
`in a predictable,
`S-ASA pharma-
`cokinetic
`profile
`similar
`to half
`the dose of sulphasala-
`
`

`
`Table 3 Transdermrrl
`
`drug delivery systems (patches)
`
`Indication
`
`Clonidine
`Fentanyl
`Nicotine
`
`Nitroglycerin
`Estrogen
`Comb. Estrogenlprogestagen
`Pilocarpine
`
`Hypertension
`Pain
`cessation
`Smoking
`Ulcerative Colitis
`Angina
`pectoris
`Estrogen
`substitute
`Osteoporosis
`Motion
`sickness
`
`Relevance
`
`Clinical
`Literature
`
`WI
`
`treatment
`very relevant, no other
`++ Clinically
`relevant, when other
`treatment
`+
`Clinically
`drug absorptions)
`[86].
`disturbed
`attractive,
`but other
`treatment
`+/- Clinically
`-
`Doubt about
`the clinical effectiveness.
`
`options are available.
`
`available.
`options
`options are sometimes
`
`not applicable
`
`(nausea, vomiting,
`
`Cl,
`
`systems with
`delivery
`drug
`[15]. Controlled
`zine
`mesalazine
`itself is another
`option
`to get a high con-
`centration
`of 5-ASA
`into
`the colon
`[16]. Two
`thera-
`peutic
`systems
`are
`available:
`individually
`coated
`microgranules
`compressed
`into
`tablets with an ethyl-
`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-
`ent dosage
`forms can be expected
`(Tabel 1) the effi-
`cacy of all
`the preparations
`is comparable
`[I 71. pH-
`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
`[18 191.
`
`Laxatives
`
`is the
`
`laxative
`
`cleavage
`of bacterial
`example
`Another
`action by anthracene
`derivatives.
`Senna preparations
`contain
`anthracene
`as glycosides.
`Hydrolization
`by
`the colon
`release
`the active anthraquinones
`[14].
`The synthetic
`laxative sodiumpicosulfate
`ed by the arylsulfatase
`activity
`in the colon
`the
`‘active’
`compound
`3 (p-hydroxyphenyl)
`yl-methane.
`is
`the colon
`in
`the cleavage
`value of
`The clinical
`that
`the drug acts than on the site of action and does
`not give
`local
`irritation
`in the stomach
`or small
`intes-
`tine.
`
`derivatives
`flora
`can
`
`is degrad-
`lumen
`to
`pyrid-2-
`
`Nicotine
`
`transdermal
`
`delivery
`
`has been shown
`In trials nicotine
`effective
`in colitis. The
`transdermal
`option
`to release
`the
`relapse of colitis
`stopped
`smoking.
`Futhermore
`it seems effective
`colitis (Table 3).
`
`to be moderately
`route
`seems an
`in patients who
`
`in steroid
`
`resistant
`
`Steroids
`
`the clinical effect
`(IBD)
`bowel disease
`In inflammatory
`of 5-ASA preparation
`is sometimes
`too weak, especial-
`
`for
`has been
`disease. Oral prednisolon
`ly in Crohn’s
`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-
`costeroids
`are offset by troublesome
`and sometimes
`irreversible
`systemic side effects
`[20].
`of the
`Budenoside
`seems
`to be the most promising
`slow
`new
`fluorinated
`glucocorticosteroids.
`A refined
`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-
`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&D-glucuronide
`is not absorbed
`in
`the
`intestine
`but hydrolyzed
`by the colonic
`bacterial
`and
`mucosal
`II-glucuronidase.
`When
`entering
`the colon,
`free budenoside
`is delivered.
`Budenoside
`absorption
`is very
`low and when
`it is absorbed
`it is rapidly metab-
`olized
`in the
`liver
`to nearly
`inactive metabolites
`which
`have only <I%
`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-R-D-glucoronide
`seems to be the
`drug of choice
`for the future
`in this clinical condition.
`Other
`therapeutic
`options
`for advanced
`drug deliv-
`ery
`in gastroenterology
`are: new pancreatic
`enzyme
`preparations.
`These preparations
`are of clinical
`value
`because
`they are not prone
`to degradation
`by gastric
`juice.
`targetting
`Selective
`patients with
`chronic
`option
`[22].
`
`for
`liver
`the
`in
`of antivirals
`hepatitis
`is an experimental
`
`[23]
`Cardiology
`is a well established
`buccal nitroglycerin
`Traditionally,
`in the
`treatment
`of episodic angina
`pec-
`dosage
`form
`toris. However,
`inconvenience
`of the buccal dosage
`forms e.g.
`irritation,
`interference
`with eating and
`talk-
`ing, has stimulated
`research
`to other
`forms of delivery
`and
`today
`three other dosage
`forms of nitroglycerin
`
`

`
`a dermal
`(patch)
`
`preparation,
`and a spray
`
`transdermal
`a
`for rapid onset of
`
`are available:
`delivery
`system
`action.
`are sus-
`formulations
`cardiac
`the newer
`Most of
`This permits a lower
`tained
`release oral
`formulations.
`dose
`frequency
`(which
`promotes
`compliance),
`a
`lower
`incidence
`of side effects and an enhanced
`ther-
`apeutic profile. Most advanced
`dosage
`forms are used
`in anti-hypertensive
`drugs
`and anti-angina1
`drugs.
`Recently, an oral novel delivery
`system with
`release of
`verapamil mimicking
`a physiological
`pattern was eval-
`uated.
`It was shown
`that
`the novel delivery
`system of
`verapamil
`administered
`nocturnally
`produced
`chang-
`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].
`is to get
`therapy
`Another
`goal of antihypertensive
`the blood
`pressure
`peak and
`through
`levels within
`certain
`limits.
`The
`through-peak
`ratio
`should
`be
`[26].
`40%
`forms can ful-
`release dosage
`The use of controlled
`the controlled
`the criteria.
`In Table 2 some of
`fill
`release preparations
`useful
`in cardiovascular
`disease
`are presented.
`the
`that
`fact
`the
`is
`Most
`important
`can be administered
`release
`preparation
`is important
`for patient
`twice a day which
`for this type of drugs
`[27].
`
`controlled
`once
`compliance
`
`or
`
`Pain
`
`treatment
`
`Opioids
`
`forms
`release dosage
`of controlled
`introduction
`The
`treat-
`of morphine
`permits a round-the-clock
`effective
`that
`ment of cancer
`pain. Years ago
`it was a myth
`morphine
`could
`not
`be
`administered
`orally.
`Intractable
`pain can be treated
`today with controlled
`release morphine
`and
`this
`is the mainstay
`of pain
`treatment
`in cancer
`pain and,
`sometimes,
`in non-
`malignant
`pain
`[28]. The biological
`availability
`of the
`different
`controlled
`release morphine
`preparation
`(MS-Contin@,
`Noceptin@,
`Kapanol@)
`is comparable,
`so the cheapest
`is the best.
`of opioid
`is the delivery
`Another
`new exciting
`area
`route[26].
`This permits
`by the epidural
`or
`intrathecal
`and
`fewer
`side effects.
`lower
`dosage
`of morphine
`Other
`drugs
`used by
`the spinal
`route
`are
`fentanyl,
`sufentanil
`and buprenorphine.
`A transdermal
`thera-
`peutic
`system of
`fentanyl
`has been
`recently
`devel-
`oped
`(see section Transdermal
`Drug Delivery). More
`experimental
`are morphine
`controlled
`release prepar-
`ations
`from microspheres
`as a site-specific
`delivery
`form
`[30], and
`the
`intranasal
`administration
`of fenta-
`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
`[321.
`is poorly
`of morphine
`administration
`rectal
`The
`and
`that
`is probably
`the
`reason why
`its
`documented
`clinical
`use so far has not yet been established.
`There
`are preliminary
`notes
`that
`rectal
`administration
`of
`
`in
`
`the
`[33]. Concerning
`is useful
`tablets
`MS-Contin
`profile methadone
`of
`the absorption
`predictability
`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
`[35 361.
`seems valuable
`citrate
`fentanyl
`Oral
`transmucosal
`pain
`in children
`under-
`as premeditation
`to prevent
`going
`small surgical
`interventions
`and
`for dermato-
`logic painfull
`procedures
`[37
`381.
`
`Local anesthetics
`
`solu-
`local anesthetic
`to
`of epinephrine
`The addition
`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-
`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-
`cal introduction
`[39].
`
`NSAlDs
`
`anti-
`of non-steroidal
`formulations
`release
`Controlled
`to flat-
`drugs
`(NSAIDs) were developed
`inflammatory
`circa-
`ten the plasma concentration
`curve, minimizing
`toxicity
`dian
`variation,
`preventing
`gastro-intestinal
`and,
`last but not
`least, rendering
`drug administration
`more
`convenient
`for
`the patients
`by
`reducing
`the
`number
`of daily doses [40].
`the onset of
`control
`Enteric-coated
`preparations
`acid-resistant
`absorption.
`In most cases the protective
`coating
`delays
`the desintegration
`and dissolution
`of
`the
`tablet until
`it reaches
`the duodenum.
`But, unfor-
`tunately,
`the prevention
`of
`local
`irritation
`does not
`seem
`to contribute
`importantly
`in the prevention
`of
`gastric ulceration
`and gastro-intestinal
`bleeding.
`The
`inclusion
`of piroxicam
`in a B-cyclodextrine
`(Brexine@) matrix
`seems an attractive
`feature
`in pre-
`venting
`gastric
`irritation. However,
`in clinical studies
`it
`was shown
`that systemic effects of the NSAlDs are the
`most
`important
`markers
`for
`gastrointestinal
`side
`effects
`[41 421.
`was
`indomethacin
`system with
`An osmotic
`pump
`Kingdom
`and The
`the United
`briefly marketed
`in
`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,
`an unusually
`high number
`of spontaneous
`reports of serious gastrointestinal
`side
`effects
`led
`to withdrawal
`from clinical
`use. The con-
`centrated
`local
`corrosive
`action
`together
`with
`an
`enhanced
`enterohepatic
`recirculation
`(through
`increased
`systemic
`bio-availability)
`of
`indomethacin
`were probably
`responsible
`for
`the higher
`gastrointes-
`tinal
`toxicity.
`release systems are frequently
`controlled
`Multi-unit
`used
`for NSAlDs. 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:
`
`

`
`indomethacin)
`(capsules with slow-release
`Indocid-R
`and Orudis
`retard
`(tablets)
`and Oscorel with
`slow-
`release ketoprofen.
`controlled
`for
`factor
`important
`Thus,
`the most
`‘easier
`to
`and
`is the
`‘convenience’
`release
`in NSAlDs
`remember’
`to prevent multiple
`daily dose. The pre-
`vention
`of gastrointestinal
`side effects by controlled
`release NSAlDs
`is a false claim.
`
`route. Now
`for asthma was given by the oral
`cation
`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,
`R-agonists
`and
`ipratropium.
`The use of
`inhaled
`drugs
`seems a very
`effective,
`relatively
`safe, method
`for all patients with
`asthma or COPD.
`
`and psychiatry
`Neurology
`disease are
`epilepsy
`and Parkinson’s
`In neurology,
`forms.
`For
`modalities
`for controlled
`release dosage
`most of the anti-epileptic
`drugs
`there
`is a clear
`rela-
`tion between
`blood
`levels and clinical effect and
`tox-
`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-
`tions with controlled
`drug delivery are now marketed:
`valproic
`acid
`(Depakine
`Chrono@)
`and
`carbamaze-
`pine
`(Tegretol CR). Most
`important
`is the prevention
`in
`of (very)
`low blood
`levels of the anti-epileptic
`drug
`the morning
`(dip),
`thus
`better
`preventing
`(‘early
`morning’)
`insults.
`of
`treatment
`to drug
`central
`Levodopa
`remains
`with
`in combination
`It is given
`Parkinson’s
`disease.
`inhibitor
`such as car-
`peripheral
`dopa-decarboxylase
`bidopa
`(in co-careldopa:
`Sinemet@
`) or benserazide
`(in co-beneldopa:
`Madopar@). To minimize
`unwanted
`effects such as nausea, vomiting
`and postural
`hypo-
`tension
`the drug
`is started at a low dose of about 125
`500 mg daily
`in divided
`doses with a conventional
`preparation.
`Modified-release
`levodopa
`preparations
`slow
`the absorption
`of
`levodopa
`and produce
`pro-
`longed
`and steady-state
`plasma concentration
`of the
`drug. Modified
`release preparations
`of both co-carel-
`dopa
`(Sinemet
`CR) and
`co-beneldopa:
`(Madopar
`HBS) are available.
`and
`off time’
`‘wearing
`reduce
`These
`formulations
`for this reason many patients prefer
`them
`to standard
`preparation.
`For clinical
`reasons
`- when
`symptoms
`become more
`severe
`- a combined
`approach
`with
`both
`standard
`and modified
`release preparation
`is
`used. To prevent
`nocturnal
`akinesia,
`slow
`release
`properties may also be an advantage
`[43].
`for anti-
`The usefulness of controlled
`drug delivery
`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 the plain
`lithium
`carbonate
`tablets.
`For antidepressant
`drugs
`the controlled
`release princi-
`ple
`is of minor
`importance
`(relevance:
`only
`to
`improve
`patient
`compliance).
`in non-
`Depot antipsychotic
`drugs are very useful
`compliant
`patients with schizophrenia.
`Patients show
`fewer
`relapses when
`continuous
`treatment
`is used.
`One of the problems
`is the patient
`selection
`to estab-
`lish the need
`for prophylactic
`anti-psychotics
`[44].
`
`and COPD
`Asthma
`for the@
`release preparations
`The use of controlled
`phyline
`is well established
`because
`they permit
`once
`or twice daily dosages. The flattened
`absorption
`pro-
`file may prevent
`side effects which are associated with
`peak
`levels. More
`than
`ten years ago nearly all medi-
`
`application
`to prepare
`
`gel
`of prostaglandin
`the cervix
`for deliv-
`
`is
`the
`[45].
`years
`
`and obstetrics
`Gynaecology
`control
`for birth
`The use of
`lntra Uterine Devices
`for
`of
`copper
`well
`established.
`The
`release
`for birth
`control
`Copper-T
`IUD
`is very effective
`IUD release of prostagens
`has been abandoned
`ago.
`intravaginal
`Local
`is an effective method
`ery.
`in post-menopau-
`of osteoporosis
`In the prevention
`of estrogen
`seems
`sal women,
`the supplementation
`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-
`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
`[461.
`or
`(with
`of estrogens
`delivery
`drug
`Transdermal
`is another
`option
`for estrogen
`without
`progesterone)
`are no comparative
`studies
`to
`substitution.
`There
`show whether
`transdermal
`drug
`delivery may give
`more compliance
`compared
`to an oral dosage
`form.
`
`Surgery
`for orthopedic
`antibiotics
`The efficacy of prophylactic
`implant
`surgery
`is well established.
`Failure
`to use anti-
`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].
`Centamicin-loaded
`cement
`(mostly
`polymethylmetha-acrylate
`cement)
`yielded
`high
`levels of the antibiotic
`in wound
`drain-
`age fluid
`for several days after operation.
`in clini-
`Antibiotics
`which are used
`in bone cement
`cal practice
`are gentamicin
`(Palaces@),
`tobramycine,
`vancomycine,
`ciprofloxacin
`and colistin with eryth-
`romycine
`(Simplex@)
`[48 491.
`treat-
`for
`cement
`Recently,
`biodegradable
`bone
`intro-
`was
`ment
`and
`prophylaxis
`of osteomyelitis
`impregnated
`duced
`[50].
`Biodegradable
`collagen
`with gentamicin
`(Caracol@)
`is used
`in the
`treatment
`of osteomyelitis
`and as an adjuvant
`in injected
`total
`hip
`replacements
`and
`in groin wound
`infections
`[51
`521.
`of vas-
`complication
`is the most dreaded
`Infection
`especially
`when
`the
`cular
`reconstructive
`surgery,
`aorta
`is involved.
`Thus,
`in vascular surgery prosthetic
`graft
`infection
`should
`be prevented
`at any price
`[53].
`The development
`of infection-resistant
`vascular pros-
`theses may be very useful
`to
`reduce
`the morbidity
`and mortality
`for excision
`or extra anatomic
`recon-
`struction
`of infected prostheses.
`sealed Dacron
`Antibiotic-loaded
`gelatin or collagen
`Teflon
`grafts
`are
`used
`in
`clinical
`practice.
`or
`Rifampicin-loaded
`gelatin-sealed
`Dacron grafts seems
`
`

`
`[54 551.
`for clinical practice
`the most reliable
`to
`Coating
`of external
`vascular
`catheters
`is used
`prevent
`bacterial
`adhesion
`and colonization
`of bacte-
`riae [56].
`intravascu-
`insertion
`after
`The surface of a cannula
`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.
`of
`heparinization
`of microbes,
`To prevent adhesion
`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
`been
`tested
`(in vitro) on a hydrophilic-coated
`cath)
`catheter.
`The
`adherence
`of
`Staphylococcus epidermidis was significantly
`compared
`to standard
`external
`polyurethane
`[581.
`of the catheters with antibiotics
`coating
`Although
`plus minocyclin)
`seems
`to prevent
`colon-
`(rifampicin
`ization
`of slime-producing
`staphylococci,
`non-antibi-
`otic coatings
`seem more attractive
`in terms of induc-
`tion of avoiding
`antibiotic
`resistance
`[59].
`
`has
`(hydro-
`strains
`of
`reduced
`catheter
`
`Ophthalmology
`for
`inserts
`the ocular
`reviewed
`Recently,
`Seattone
`In the clinical practice of the oph-
`drug delivery
`[60].
`a
`few
`advanced
`drug
`delivery
`talmologist
`only
`systems are available.
`the anti-glau-
`to deliver
`insert
`Ocusert@
`is an ocular
`with a constant
`rate
`in the
`coma drug,
`pilocarpine,
`eye. Potentially,
`the Ocusert@
`type of delivery
`is useful
`for anti-microbials,
`anti-virals,
`anti-fungals,
`anti-aller-
`gians and NSAlDs. The classical eye drops have only a
`short duration
`of action which makes
`it necessary
`to
`administer
`this drugs
`4-8
`times a day, so Ocusert*
`systems seems
`to overcome
`this frequent
`administra-
`tion.
`(water)
`of poorly
`problems
`solubility
`To overcome
`nanoparticles
`for
`soluble
`drugs, microspheres
`and
`development
`[61].
`ocular delivery
`systems are under
`Poor
`cornea1
`penetration
`of drugs
`has promoted
`research on ocular application
`of liposomes
`[62].
`Infections
`of cytomegalovirus
`(CMV)
`in the eye and
`accompanying
`blindness
`seen
`in patients with AIDS
`have stimulated
`the
`research
`of
`intraocular
`applica-
`tion of ganciclovir
`and
`foscarnet.
`Intraocular
`implan-
`tation
`of a ganciclovir
`device
`seems promising,
`but
`studies are ongoing
`to establish
`its final place
`in thera-
`PY [631.
`
`disease and oncology,
`Infectious
`in
`systems
`The application
`of
`liposomes
`as delivery
`the prevention
`and
`treatment
`of
`infectious
`diseases
`has recently
`been
`reviewed
`in this
`journal
`[64]. The
`first anti-infective
`liposomal
`drug which
`is introduced
`It
`in clinical practice
`is amphotericine
`B (Ambisome@).
`has at
`least some
`theoretical
`advances
`over classical
`amphotericine
`B deoxycholate:
`from animal
`experi-
`ments
`it has
`an
`enhanced
`clinical
`effect with
`decreased
`toxicity
`to
`the kidneys,
`but
`till now
`its
`
`has only been sub-
`profile
`toxicity
`and
`effectiveness
`[65]. A cumulative
`dose of
`trials
`ject
`in uncontrolled
`approximately
`4 g (2.8 mg/kg) will cost at least %US
`12,500
`[66].
`the
`are
`liposomes
`of
`applications
`Other
`potential
`tox-
`inclusion
`of ge