Prodrugs for nasal drug delivery

LAdvanced Drug Delivery Reviews 29 (1998) 135–146

Prodrugs for nasal drug deliverya b ,*Ramesh Krishnamoorthy , Ashim K. Mitra

aBausch & Lomb Pharmaceuticals, 8500 Hidden River, Parkway, Tampa, Florida, FL 33637, USA

bDepartment of Pharmaceutical Sciences, University of Missouri-Kansas City, 5100 Rockhill Road, Kansas City, MO 64110-2499, USA

Received 10 October 1996; accepted 4 March 1997

Abstract

Recently, the delivery of xenobiotics via the nasal route has received increasing attention as this offers several advantages,i.e. high systemic availability, rapid onset of action. Both charged and uncharged forms of drugs can be transported acrossthe nasal epithelium. This mucosa is rich in various metabolizing enzymes such as aldehyde dehydrogenase, glutathionetransferases, epoxide hydrolases, cyt-P450-dependent monooxygenases. The presence of these enzymes may make it possiblefor pharmaceutical scientists to design prodrugs for better absorption and high systemic availability. Recent advances inpeptide nasal delivery through prodrug modification has been thoroughly discussed in this paper. Finally, nasally deliveredtherapeutic agents targeted to various disease states have been examined. 1998 Elsevier Science B.V.

Keywords: Bioreversible derivatives; Enhancement; Peptides; Barriers; Mechanisms

Contents

1. Introduction ............................................................................................................................................................................ 1362. Barriers to nasal drug delivery.................................................................................................................................................. 1363. Prodrug approach to peptide absorption .................................................................................................................................... 137

3.1. Considerations in the design of prodrugs for nasal delivery ................................................................................................. 1394. Parameters affecting nasal absorption ....................................................................................................................................... 139

4.1. Effect of solution pH ........................................................................................................................................................ 1394.2. Effect of the drug lipophilicity .......................................................................................................................................... 139

5. Examples of nasal uptake of representative model drugs ............................................................................................................ 1395.1. Adrenal corticosteroids ..................................................................................................................................................... 1405.2. Sex hormones .................................................................................................................................................................. 1405.3. b-Adrenoceptor blocking agents........................................................................................................................................ 1405.4. Narcotics and antagonists ................................................................................................................................................. 1415.5. Barbiturates ..................................................................................................................................................................... 1415.6. Cardiovascular drugs ........................................................................................................................................................ 1415.7. Antibiotics....................................................................................................................................................................... 1415.8. Antiviral agents ............................................................................................................................................................... 1425.9. Antihistamines ................................................................................................................................................................. 1425.10. Central nervous system stimulants ................................................................................................................................... 1425.11. Miscellaneous agents ...................................................................................................................................................... 142

6. A case study of nasal drug absorption enhancement ................................................................................................................... 1437. Conclusion ............................................................................................................................................................................. 144References .................................................................................................................................................................................. 144

*Corresponding author.

0169-409X/98/$19.00 1998 Elsevier Science B.V. All rights reserved.PII S0169-409X( 97 )00065-3

136 R. Krishnamoorthy, A.K. Mitra / Advanced Drug Delivery Reviews 29 (1998) 135 –146

1. Introduction nasal drug delivery is to overcome barriers posed bythe nasal mucosal lining and the enzymes present in

Promising results with enhanced bioavailability the nasal cavity.have been obtained upon nasal administration and It has been demonstrated that for uncharged drugs,have prompted more extensive investigations in this the nasal mucosal membrane behaves as a modifiedarea. The nasal route of administration, among other lipophilic transport barrier [10]. Transport of chargedpromising nonparenteral routes, may very well drugs such as alkanoic acids under basic pH con-satisfy the prerequisites for nonoral, nonparenteral ditions may be dependent on the microenvironmentsystemic medication purposes. The systemic bio- pH effects due to the complex architecture of theavailability and thus the efficacy of drugs is quite nasal passages. In addition, the nasal uptake of theoften influenced by their route of administration [1]. charged molecules may be influenced by both theThis is especially true when the drug is subject to multicompartment mucus layer and the underlyingmetabolic clearance prior to its reaching the target epithelial membrane, each with a different equilib-organ via systemic circulation. This accounts for the rium concentration or permeability characteristics.low oral bioavailability of drugs like morphine [2], The anatomy of the nasal mucosal barrier suggeststerbutaline [3] and propranolol [4]. For instance, that several separate compartments may contribute tonasal delivery of propranolol and several sex hor- permeability conditions for the transnasal passage ofmones resulted in rapid and complete absorption drugs. The existence of the aqueous boundary layer[5,6]. This could well be ascribed to avoidance of may influence the transnasal absorption of a wholegastrointestinal metabolism and first-pass clearance, host of drugs, both lipophilic and hydrophilic [11].both of which could result in compromised bioavail- The nasal epithelial mucosa is covered withability. numerous microvilli, resulting in a large surface area

During the past several decades, the feasibility of available for drug absorption and transport. How-drug delivery via the nasal route has received ever, the ability of the nasal tissues to metabolizeincreasing attention from pharmaceutical scientists drugs is something that cannot be overlooked [12].and clinicians. Drug candidates ranging from small Various enzymes have been found to exist in sub-metal ions to large macromolecular proteins have stantial amounts in the nasal mucosa, i.e. aldehydebeen tested in various animal models [7]. It has been dehydrogenase, glutathione transferase, epoxide hy-documented that nasal administration of certain drolases, cytochrome P-450-dependent monooxygen-hormones and steroids have resulted in a more ases, carboxylesterases. Other enzymes such ascomplete absorption [5,6]. This indicates the po- aminopeptidases have been shown to result in pre-tential value of the nasal route for administration of systemic degradation of peptides and proteins [13].systemic medications as well as utilizing this route The cytochrome P-450 activities in nasal micro-for local effects. somes has been shown to be active in catalyzing the

The nasal route of drug delivery has advantages oxidation of certain substances. Numerous com-over the other alternative systems of non-invasive pounds have been shown to be metabolized in vitrodrug administration. It is apparent that the nasal by the nasal P-450-dependent monooxygenase sys-mucosa is permeable to more compounds than the tems, e.g. nasal decongestants, essences, anesthetics,gastrointestinal tract due to lack of pancreatic and alcohol, nicotine and cocaine [14]. Other xenobioticgastric enzymatic activity, neutral pH of the nasal metabolizing enzymes of the nasal cavity, includemucus, and less dilution by gastrointestinal contents. flavin-containing monooxygenase, alcohol and alde-Above all, nasally administered drugs avoid hepatic hyde dehydrogenases [15,16]. Carboxylesterases arefirst-pass effect, making this a favored route for another class of enzymes which have the highestpotentially degradable agents by the hepatic system. activity reported in the nasal epithelia [17,18]. These

enzymes are believed to play a major role inindustrial ester-induced lesions. Other enzymatic

2. Barriers to nasal drug delivery barriers prevalent in the nasal tissues include, epox-ide hydrolases [19], UDP-glucuronyl transferase

Nasal administration of drugs has been extensively [20,21], glutathione transferase [22,23].reviewed [8,9]. One of the biggest challenges to Nasal delivery of peptides and proteins is deemed

R. Krishnamoorthy, A.K. Mitra / Advanced Drug Delivery Reviews 29 (1998) 135 –146 137

superior to the oral route of administration, due to across biological barriers, and premature metabolismlack of proteolytic enzymes and extreme pH con- to inactive species [33]. The term prodrug was firstditions. Several different barriers exist to hamper coined by Albert in 1951 [34] to describe compoundsnasal protein uptake, e.g. rather tight cellular com- which undergo biotransformation prior to exhibitingpositions (physical barrier in the form of tight their pharmacological effects. Though this term hasjunctions), and the presence of peptidases, proteases been expanded in this present day to include com-and proteinases. Homogenate studies have indicated pounds that undergo chemical transformations, theboth the presence of exopeptidases and endopeptid- basic working concept has remained unchanged [35].ases [13,24]. Aminopeptidases have been indicated Today the prodrug chemistry encompasses mostin the degradation of leucine enkephalins. To over- areas of synthetic organic chemistry whose focus iscome these barriers, compounds like boroleucine, on improving physicochemical needs and thereby thebestatin and puromycin have been shown to work as biological properties of the parent moiety in aaminopeptidase inhibitors [25]. Faraj et al. [26] transient fashion. This is all towards an end tosimilarly found that bile salts are able to inhibit nasal overcome the intrinsic properties associated with thepeptide activity against leucine enkephalin in vitro. therapeutic use of the parent drug.

Although extensive information concerning these Invariably the problems inherent in the parentbarriers are available, a systematic effort to identify molecule can be traced back to a particular func-the mechanisms of absorption enhancement is still tional group(s). Thus, the obvious solution to thelacking. In summary, it can be stated that there are problem appears to involve transient modification bysome general guidelines that may be adhered to masking or covering that functional group(s) withenhance drug delivery when opting for a non-inva- another functional group (referred to as the ‘promoi-sive route such as the nasal route: ety’) [36]. This combination of the two functional

(a) Minimizing metabolism: this could be achieved groups results in the formation of a new entity whichby chemical modification (i.e. chemical derivatiza- usually exhibits unique physicochemical properties.tion) [27,28], covalent bonding to a polymer back- Yet this combination has the complete potential ofbone, encapsulation into a protective material, coad- reverting back to the parent components in vivo orministration with an enzyme inhibitor or pretreat- under suitable limiting conditions. This union ofment with an enzyme inactivator [29]. functional groups to give rise to a new molecular

(b) Increasing absorption: this could be accom- entity is referred to as a ‘prodrug’. A classic exampleplished via use of prodrugs, chemical modification of is the combination of an alcohol functionality in thethe parent molecule (such as salt or ester formation parent drug with a carboxylic acid functional groupfor better transnasal permeability) [30], use of phys- in the promoiety to give rise to an ester functionalical methods, use of permeation or absorption en- group (prodrug) which can be readily hydrolyzed tohancers, or transient disruption of the nasal epithelial its components in vivo by esterases. This examplemembrane (such as incorporation of surfactants into will become the prime focus of all our discussion.nasal dosage forms) [31]. A number of surfactants The entire promoiety and not just the enablinghave been reported to enhance the absorption of functional group must be considered in the design ofdrugs through the nasal mucosa to levels sufficient to an appropriate prodrug to exhibit certain desirableachieve their systemic effects. physicochemical properties. Specific examples of

(c) Prolonging residence time in the nasal cavity prodrugs commonly used for nasal drug deliveryby increasing the viscosity of the vehicle, use of include esters of steroids (e.g. beclomethasone dip-bioadhesives or other suitable formulation changes ropionate monohydrate, flucionide dipropionate),[32]. charged prodrug compounds (e.g. sodium salt of

cromoglycic acid), and prodrugs of some peptides(e.g. desmopressin acetate).

3. Prodrug approach to peptide absorption Most prodrugs can be divided into two generaltypes. The first general type of prodrugs is one in

Historically, prodrugs have been used to overcome which one of the functional groups that gives thebad taste, poor solubility, insufficient stability (both promoiety its characteristic physicochemical andchemical and enzymatic), incomplete absorption biological properties is directly attached to the


functional group in the parent drug that is to be and specificity, and its preferred route of administra-transiently masked. The second general type of tion. Thus, in the design of a suitable prodrug orprodrug is one in which the functional group in the analogue, achieving a suitable structure for a givenpromoiety is separated from the functional group in molecule frequently necessitates a three-way com-the parent drug by a methylene group or a vinylog- promise as to its aqueous solubility, lipophilicity,ous methylene group. The functional groups that size, and assurance that it will be adequatelyhave been incorporated into the promoieties that protected from enzymatic degradation.form the prodrugs have been shown to be capable of Nishihata, in a Japanese patent (JP 92-220028increasing both the lipid solubilities as well as the 920819), has discussed the preparation of enamineaqueous solubilities. The balance between the two derivatives of peptides as prodrugs. In these, thedepends on the incorporated functional groups. N-terminus amino group or amino group residue is

The full potential for the use of prodrugs in converted into enamine or pharmaceutically accepteddifferent arenas and for optimizing the needs for salt thereof. The peptides selected in the examinationdifferent routes of delivery has yet to be completely included, angiotensin II, bradykinin, caerulein, car-realized. The breadth of the possible transient nosine, enkephalin, Met-enkephalin, Leu-enkephalin,changes is limited only by the imagination and kalidin, vasopressin, insulin, calcitonin, and com-resourcefulness of the individuals for designing the pound U-72102E. These agents have been shown toprodrug and for the use it is intended. This technique have promise as anti-hypertensive agents. Similarly,has not reached its maturity and certainly a lot of prodrug derivatives of enkephalins have been de-work is yet to be performed in this field to ascertain signed to reduce aminopeptidase-catalyzed metabo-its fullest promise. lism. Rasmussen and Bundgaard concluded that 4-

A major obstacle to the application of peptides in imidazolidinone derivatives of enkephalin may be aclinical settings is their poor biomembrane penetra- useful prodrug approach to protect N-terminal aminotion, rapid enzymatic degradation, and short bio- acid residue of enkephalins against cleavage bylogical half lives. A possible approach that has been aminopeptidases and to obtain transport forms withsuggested for a variety of peptide agents to solve improved lipophilicity [40].these delivery problems is derivatization of peptides The ideal prodrug of a peptide would exhibitto produce prodrugs or transport forms that are as enhanced membrane permeation characteristics andlipophilic as the parent peptides and capable of increased stability against metabolic degradation.protection against degradation by enzymes. The After crossing the membrane barrier, the prodrugpotential utility of the prodrug approach to protect should undergo spontaneous or enzymatic trans-peptides has been discussed with examples in this formation to release the peptide, which then canreview [37]. Huang has demonstrated the utility of exhibit its pharmacological effect. It was shown that,this approach for drug delivery via the nasal route by preparing cyclic prodrugs using the functional[38]. groups of the N- and C-terminal ends of a peptide,

The nasal absorption of L-tyrosine and the effect metabolic degradation mediated by exopeptidasesof structural modification on that absorption have should be minimized [41]. In addition, cyclization ofbeen studied using an in situ experimental technique a peptide may also restrict the conformation flexibili-[28]. It was assessed that the carboxylic acid esters ty of the molecule, leading to a more compactwere absorbed 4–10 times faster than L-tyrosine. The structure with altered physicochemical propertiesdifference in rates could not only be ascribed to [42]. Recently, a cyclic acyloxyalkoxycarbamatedifference in octanol–water partition coefficients, but prodrug of a model hexapeptide (H–Trp–Ala–Gly–rather to lack of negative charge on the carboxylate Gly–Asp–Ala–OH) was synthesized to enhance themoiety. Barlow and Takashi [39] have proposed a membrane permeation of the peptide and stabilize itsystematic approach in the design of peptide ana- to metabolism. It was concluded that a cyclic peptidelogues for improved absorption. In their opinion, the using an acyloxyalkoxy promoiety reduced the labili-choice of strategy employed in designing a peptide ty of the peptide to peptidase metabolism anddrug requires consideration of the demands imposed substantially increased its permeation through bio-by the parent peptide, its site of action, its potency logical membranes [43]. The conformation of the


cyclic prodrugs of a peptide is also a determinant in 4.2. Effect of the drug lipophilicitythe increased permeability of this prodrug. It wasshown that the increased ability of the above cyclic The rate and extent of drug absorption of a drugprodrug to permeate membranes compared to the across a biological membrane is influenced by itsmodel hexapeptide could be due to reduction in the lipophilicity. Studies on the nasal delivery of a seriesaverage hydrodynamic radius of the molecule of progestational steroids in ovariectomized rabbitsfacilitating paracellular flux and/or the reduction in demonstrated that the octanol–water partition coeffi-the hydrogen bonding potential facilitating trans- cient does not reflect the lipophilicity of progesteronecellular flux [44]. and its hydroxy derivatives and predict their parti-

Based on this brief overview and pioneering work tioning behavior in the nasal mucosa. In addition, thedone in this area by Bundgaard, it has been shown stereochemical conformation during membrane trans-that prodrugs of peptides are a feasible technology port is important for adequate nasal drug absorption.which may offer promise to overcome the enzymatic Because the physicochemical properties of theand penetration barriers in the delivery of these drugs themselves are usually not optimal for theirpotent compounds. This could range from derivatiza- delivery using the conventional route, alternatetion of the peptide bond itself, C-terminal amide routes like the nasal route may be chosen. Even thisgroup, the tyrosine phenol group in tyrosyl peptides route may become formidable in light of theand the N-terminal amino group. More work needs inadequacy that the physicochemical properties ofto be done to further improve our understanding of the drug may impose and thus is not always effec-means and ways to enhance delivery of these agents tive. There are multiple approaches that can be takenvia this route. in dealing with this issue. One of them is to use a

different formulation to deliver the drug. Here,permeation enhancers, absorption modifiers and

3.1. Considerations in the design of prodrugs for agents to transiently modify the nasal epithelialnasal delivery barrier may be used to enhance drug uptake. The

alternate approach is to make a new drug entity, or aAs with the development of pharmaceutical dos- new analog or homolog of the original drug. The

age forms for a drug, an adequate assessment needs new molecular entity exhibiting the desired physico-to be made with regards to the physical, chemical chemical properties are used. The third approach isand biopharmaceutical properties of the desired making a transient derivative or commonly referredcandidate before a prodrug for nasal drug delivery is to as the ‘prodrug’ of the original drug.designed. The following basic physicochemical prop- The approach of making a prodrug allows one toerties need to be determined to develop a successful transiently modify the desired physicochemical prop-prodrug: (a) solubility, (b) stability, (c) compatibility, erties of drug. These changes are well characterized(d) enzymic stability, and (e) toxicity [45]. and one is left with a well-understood molecule to

work with.

4. Parameters affecting nasal absorption 5. Examples of nasal uptake of representativemodel drugs

4.1. Effect of solution pHThis section attempts to focus on some typical

The extent of nasal absorption was found to be examples of classes of compounds that have beendependent on the pH of the solution of the drug (or looked at utilizing the nasal route of drug delivery.formulation). A greater nasal absorption was Though the list is not exhaustive, it classicallyachieved at a pH lower than the pK at which the typifies some of the reasons why these agents havea

penetrant molecule exists as non-ionic species. With had more success compared to some others, delineat-increase in pH, the rate of absorption decreases ing some of the qualities that have been exploited toowing to the ionization of the penetrant molecule. enhance drug delivery by this route. Examples


pertaining to proteinaceous compounds have been attained following nasal delivery, as compared toprecluded from the discussion to simplify the matter 1.2% with the intraduodenal route. David et al. [51],and have been discussed elsewhere. using ovariectomized rhesus monkeys, sprayed pro-

gesterone with a pre-calibrated glass atomizer. A5.1. Adrenal corticosteroids significantly higher C was observed in the serummax

and CSF following nasal spray, compared to noseCorticosteroids have been used in the treatment of drops, intravenous injection, and eye drops. The

seasonal and perennial allergic rhinitis and vaso- nasal spray formulation was, therefore, superior to amotor rhinitis. Intranasal administration of cortico- nasal drop formulation indicating the importance ofsteroids has been sought to reduce the risk of the delivery mode and site of deposition in the nasalsystemic side effects associated with oral and paren- cavity. Testosterone is generally injected intramuscu-teral use. Several studies have attempted to deal with larly due to extensive metabolism in the GI andthis subject [46,47], although they were mostly first-pass effect following oral ingestion. Thelimited to the assessment of the local use of cortico- feasibility of transnasal absorption of this naturalsteroids in the nasal cavity, particularly in allergic male sex hormone was also investigated [52] in malerhinitis and hay fever. rats. The plasma concentrations of testosterone in-

creased rapidly to reach a peak level in 2 min after5.2. Sex hormones nasal administration. The duodenal route, on the

other hand, resulted in a considerably lower profile.Sex hormones are produced by the testes and The overall nasal bioavailability exceeded 90%

ovaries which control the secondary sex characteris- relative to i.v., while the intraduodenal bioavail-tics. They are used clinically in the induction of ability was found to be only 1%.hormonal contraception, when high doses are givenorally or parenterally. However, natural steroids such 5.3. b-Adrenoceptor blocking agentsas progesterone and estradiol are not effective orallydue to extensive GI degradation followed by a first- Propranolol, an adrenergic b-blocker, is usedpass clearance mechanism. Therefore, nasal adminis- clinically in the management of hypertension and thetration has been examined carefully by several treatment of angina pectoris. This compound wasresearch groups for systemic absorption [6,48–50]. found to be poorly absorbed from the GI-tract with

Kumar et al. [48] have studied the nasal uptake of immense variation among subjects. The low andtritium-labeled estradiol and progesterone in rhesus variable bioavailability (16–60%) was postulated tomonkeys. Both compounds were found to be ab- be a result of extensive degradation in the gut andsorbed intranasally and are able to penetrate into the first-pass metabolism [53]. Hussain et al. [5] ex-cerebrospinal fluid rapidly. A comparison of the amined the feasibility of administering propranololplasma:CSF ratio of the two compounds indicated intranasally to rats aimed at improving bioavail-that more steroids accumulated in the CSF after ability and minimizing variation. They demonstratedintranasal administration compared to the intraven- a rapid absorption of the drug with a peak plasmaous route. This result suggested that the two steroids concentration observed within only 5 min with thecan be absorbed from the nasal cavity and reach the nasal bioavailability of propranolol to be similar tobrain directly via the respiratory and olfactory mu- that of the i.v. administration. The same researchcosa. group then tested a propranolol formulation con-

The bioavailability of progesterone following in- taining 2% methylcellulose gel in humans. Serumtranasal, intravenous, and intraduodenal administra- propranolol profiles were found to be identical to thattions has been compared by Hussain et al. [6] using of intravenous infusion, while an oral tablet dosagerats as the animal model. Following intranasally form merely attained a bioavailability of 25% [54].delivery, plasma concentrations of progesterone in- They suggested that nasal administration of propran-creased rapidly to reach a peak level in 6 min. AUC olol appears to be superior to the oral route and asvalues were also found to correlate linearly with the effective as the intravenous route. Duchateau et al.administered doses. A bioavailability of 100% was [55,56] further studied the influence of substrate


lipophilicity on the nasal drug uptake in human 5.6. Cardiovascular drugssubjects. Two b-blockers of different lipophilicity,i.e., alprenolol and metoprolol were used for this Hydralazine is a vasodilator which is used for thepurpose. The results indicated that the more hydro- treatment of malignant hypertension and hyperten-philic drug resulted in a low bioavailability which sive emergencies, in conjunction with other anti-was not significantly different from the oral or hypertensive drugs. Oral administration results insublingual administrations. Alprenolol, on the other good absorption, however, extensive hepatic first-hand, was absorbed rapidly into the systemic circula- pass metabolism greatly limited its bioavailability.tion with a much higher bioavailability when ad- Kaneo [58] studied nasal hydralazine absorption inministered intranasally. This information suggests rats. At pH 3.0, hydralazine was found well absorbedthe importance of penetrant lipophilicity on nasal through the nasal mucosa reaching a peak level in 30drug transport. min. Hydralazine nasal absorption was determined to

be a passive and pH-dependent process, with theextent of absorption increasing as the pH was raised

5.4. Narcotics and antagonists from 3.0 to 6.5. Hirai et al. [59] also evaluated the insitu absorption of hydralazine as a function of

Buprenorphine is a synthetic opiate analgesic with perfusion pH. Their results indicated that hydralazinecombined agonist /antagonist properties. Oral ad- disappears from the nasal cavity in a first orderministration of buprenorphine produces only a low kinetics. A good relationship exists between theanalgesic potency due to the extensive first-pass absorption rate constant and the fraction of itsclearance. Hussain et al. [57] compared intranasal undissociated species. Nevertheless, even when theadministration of buprenorphine with intravenous drug exists in the ionized form, substantial absorp-and intraduodenal delivery in rats following a single tion was still observed. Aqueous channels in thedose of 135 mg/ rat. An intranasal bioavailability of nasal mucosa are suggested to play an important role9% was obtained. The authors also reported that in the transport of this compound.naloxone, a narcotic antagonist, is rapidly and com- Nitroglycerin or glyceryl trinitrate is a car-pletely absorbed from the rat nasal cavity. In- diovascular drug which has been used to abort ortraduodenal administration, on the other hand, only prevent anginal attacks. Oral bioavailability is hin-yielded a bioavailability of 1.5%. dered by the hepatic first-pass metabolism. There-

fore, sublingual tablets, topical ointments, and trans-dermal patches are preferred. It serves as an example

5.5. Barbiturates of water-soluble hydrophilic drugs that can be rapid-ly absorbed across the nasal mucosa. Hill et al. [60]

Huang et al. [27] studied the nasal absorption of a studied the nasal absorption of nitroglycerin in fiveseries of barbiturates with ranging lipophilicity, i.e. patients undergoing elective coronary artery bypassbarbital, phenobarbital, pentobarbital, and secobarbi- surgery. They found that the compound is rapidlytal. In situ rat nasal perfusion indicated that a 40-fold absorbed into the vascular space following intranasaldifference in the partition coefficient resulted in a instillation with the observed plasma levels similar tofour-fold improvement in the extent of nasal uptake. an intravenous bolus injection and higher than that ofA series of barbiturates with increasing lipophilicity sublingual administration.as demonstrated by their chloroform–water partitioncoefficients was studied by Hussain and co-workers 5.7. Antibiotics[28] using in situ nasal perfusion. These werebarbital, phenobarbital, pentobarbital, and secobarbi- Investigations have been initiated on the deliverytal. An increase in the extent of nasal absorption with of penicillin in aerosol form to the nasal accessoryan increase in lipophilicity of these compounds was sinuses for the treatment of chronic sinusitis [61].seen. This information indicated that factors other The results indicated that aerosolized penicillin is athan lipophilicity may also contribute significantly to safe, rational, and effective mode of acute infectionthe transnasal permeation of penetrants. treatment in the upper respiratory tract and paranasal


sinuses. The nasal absorption of three compounds vasoconstriction which lasted 4–6 h or longer. Inwhich are poorly absorbed from the GI tract due to patients receiving chlorprophypyridamine maleatetheir high water solubility, i.e., sulbenicillin, nasal solution, 78.8% exhibited a moderate to com-cephacetrile, and cefazolin, have subsequently been plete vasoconstriction. In another study, the combi-studied [62]. The authors found that a significant nation of phenylephrine and thonzylamine was foundamount of these compounds could be detected in to be weak as a nasal decongestant. The addition ofurine following nasal administration which was phenylpropanolamine markedly improved the effec-nearly one-half of that detected following an in- tiveness of this formulation [67].tramuscular injection. On the other hand, oral ad-ministration resulted in very poor absorption of all 5.10. Central nervous system stimulantsthree drugs. The intranasal absorption of gentamicin,a polar aminoglycoside antibiotic, has been studied Cocaine has been used in otolaryngology andby Rubinstein [63] in human subjects. A bile salt anesthesiology as a topical anesthetic and vasocon-absorption enhancer, sodium glycocholate, was strictor. It is also a major drug of abuse administeredneeded to yield detectable serum gentamicin levels. through nasal applications. The plasma cocaineThis result indicated that an absorption enhancer may profiles following intranasal topical anesthesia werebe needed to obtain significant absorption of a polar determined in 20 patients by Jatlow and Bailey [68].compound. When a 10% solution was delivered topically (1.5

mg/kg) to the nasal mucosa, the plasma cocaine5.8. Antiviral agents levels increased rapidly for the first 15–20 min,

peaked within 15–60 min and then decreased gradu-Nasal administration of antiviral agents is intended ally over the next 3–5 h. Cocaine was found to

for upper respiratory viral infections. In mice infec- remain on the nasal mucosa for as long as 3 hted with a 100 TCID50 influenza Ao, dosing of following intranasal application, probably as a resultphenyl-p-guanidino benzoate (PGB) four to five of its strong ciliostatic effect [69]. The phar-times per hour significantly inhibited viral growth macokinetics of cocaine following intranasal ad-[64]. However, it was found that the mucociliary ministration can be described by a one-compartmentclearance mechanism limited the exposure time to open model with two consecutive first-order input7.5–12.5 min only. This result provided some in- phases and one first-order elimination phase [70].formation concerning the contributory effect of The AUC values were linearly dependent on themucociliary clearance as an important factor limiting doses administered intranasally. Despite its highnasal drug absorption. Enviroxime, a benzimidazole potential of abuse, nasal cocaine administration isderivative, had also been delivered intranasally for highly desirable as a local anesthetic, in the relief ofclinical prophylactic and therapeutic effects against nasal ganglion neurosis syndrome, and in the treat-rhinovirus type 4 infection [65]. While cold symp- ment of headache and pains of the neck and shoul-toms were observed in 27–73% of the volunteers in der.different test groups, fewer symptoms were found inthe subjects who were treated with enviroxime 5.11. Miscellaneous agentsbefore rhinovirus challenge.

In addition to the chemical agents discussed5.9. Antihistamines above, other compounds have also been evaluated

for their nasal delivery potential. SodiumAntihistamines block the effects of histamine on cromoglycate, for instance, penetrates the nasal

H1-receptors. The potential of intranasal administra- mucosa far more efficiently than in the GI tract,tion of prophenylpyridamine maleate and chlor- reaching a nasal bioavailability of 60% [71]. Nasalprophypyridamine maleate was evaluated in patients administration of dopamine, on the other hand,with allergic rhinitis [66]. They found that 82% of indicated that this compound is capable of penetrat-patients receiving the prophenylpyridamine maleate ing into the CSF directly without entering the hemalnasal solution exhibited a moderate to complete nasal compartment first. Sympathomimetic drugs such as


epinephrine, ephedrine and phenylephrine have long mitoyl-DL-carnitine chloride (PCC) or DL-stearoylbeen used in the nasal dosage forms. However, they carnitine chloride (SCC) could significantly increaseare poorly absorbed across the nasal mucosa for the mucosal permeability of acyclovir across thesystemic effect [72]. nasal mucosae. The sodium glycocholate–DL-oc-

tanoylcarnitine chloride (OCC) marginally improvedthe absorption of acyclovir via the nasal route. The

6. A case study of nasal drug absorption effect of the mixed micellar solutions was synergisticenhancement and much more pronounced than that of a single

adjuvant, probably because of micellar solubilizationOver the last few years, there has been a lot of of acylcarnitines by sodium glycocholate. The mag-

attention in the area of non-invasive alternate routes nitude of absorption promotion was dependent on theof drug delivery. Our laboratory has been pioneering hydrophobicity of the acylcarnitines.in this area and has made an attempt to understand It is true that changes in nasal membrane structurethe mechanism(s) for enhancing drug delivery utiliz- is partially responsible for increasing the absorptioning this route [73–77]. One of the first references in characteristic of such poorly absorbable compoundsthe literature pertaining to utilization of bioreversible as acyclovir. A universally applicable absorptionderivatives for nasal drug delivery was use of adjuvant has yet to be identified which causesclofilium tosylate [78]. In this study it was demon- negligible mucosal damage on long-term use andstrated that the blood levels following nasal adminis- there are issues of safety. Thus, another strategy totration of this quarternary ammonium compound enhance the delivery of such compounds would bederivative was not statistically significant when the design of derivatives with high partition co-compared to intravenous administration. A similar efficients, thereby thermodynamically favoring soluteconclusion was reached with tixocortol pivalate, a partitioning into the nasal membrane. Since the ratecorticosteroid, and it was shown that when given for and extent of nasal drug uptake is dependent onshort periods of time by nonparenteral routes, it does lipophilicity of the penetrant, it was perceived thatnot induce any measurable systemic glucocorticoid formation of bioreversible prodrugs would greatlyeffect [79]. facilitate the process of absorption of these polar

Over the last 5 years, we have been investigating compounds [82]. A series of aliphatic ester prodrugsthe means of enhancing the nasal transport of a of acyclovir was synthesized to delineate theirnasally nonabsorbable hydrophilic compound, effectiveness in enhancement of transport charac-acyclovir. Acyclovir is a potent antiviral agent which teristics across the rat nasal mucosa [83]. The esteris relatively polar and demonstrates poor absorption prodrugs showed consistent increases in lipophilicitycharacteristics when given non-systemically. The with corresponding decrease in aqueous solubility asfirst set of investigations pertained to increasing a function of side-chain length. The bioconversionnasal absorption by changes in formulation strategy. kinetics of the prodrugs was dependent on both theIn a series of studies, utilizing bile salt–fatty acid apolar and steric nature of the acyl substituents.mixed micelles (which had shown promise to in- Prodrug cleavage by nasal carboxylesterases wascrease peptide absorption), it was proven that a noted for the higher derivatives, indicative of anon-linear correlation exists between first order nasal limiting scenario for maximising absorption usingabsorption rate and nasal protein release [80]. Fur- this approach.thermore, it was seen that the nasal absorption of In a subsequent paper [84], a combined strategyacyclovir was enhanced in the presence of conju- involving both structural modification and incorpora-gated tri-hydroxy bile salts and bile salt–fatty acid tion of proven absorption enhancers was investigatedmixed micelles. In a subsequent study, the use of bile to increase absorption potential. In this report, ansalt–acylcarnitine mixed micelles was investigated attempt was made to study the possible mechanisms[81]. It was observed that the acylcarnitines by responsible for improved acyclovir nasal uptake bythemselves were totally ineffective in enhancing individually examining the physical barrier integrity,nasal uptake of acyclovir. However, the mixed enzymatic barrier function, and contribution ofmicellar solutions of sodium glycocholate with pal- micellar solubilization. The study concluded that the


enhanced nasal absorption of acyclovir and its Referencesprodrugs may be the result of a reduction in themucosal resistance rather than other minor events. [1] D. Brewster, M.J. Humphrey, M.A. McCleavy, The systemic

bioavailability of buprenorphine by various routes of ad-Branching of the acyl side chain in the promoietyministration, J. Pharm. Pharmacol. 33 (1981) 500–506.appears to retard the enzymatic activity significantly.

[2] S.F. Brunk, M. Delle, Morphine metabolism in man, Clin.Therefore, the design of an ester prodrug with a Pharmacol. Ther. 16 (1974) 51–57.branched side chain may be favorable for the pur- [3] W.D. Conway, S.M. Singhvi, M. Gibaldi, R.N. Boyes, Thepose of nasal drug delivery with enhanced lipo- effect of route of administration on the metabolic fate of

terbutaline in the rats, Xenobiotica 3 (1973) 813–821.philicity and minimal presystemic degradation.[4] T. Walle, T.C. Fagan, E.C. Conradi, U. Walle, T.E. Gaffney,As a final piece to the better understanding of

Presystemic and systemic glucuronidation of propranolol,prodrug design for intranasal drug delivery, the Clin. Pharmacol. Ther. 21 (1979) 167–172.biodegradation characteristics of acyclovir 29-esters [5] A.A. Hussain, S. Hirai, R. Bawarshi, Nasal absorption ofby respiratory carboxylesterases was studied [85]. In propranolol in rats, J. Pharm. Sci. 68 (1979) 1196–1199.

[6] A.A. Hussain, S. Hirai, R. Bawarshi, Nasal absorption ofvitro studies confirmed that the enzyme responsiblenatural contraceptive steroids in rats-progesterone absorp-for ester prodrug breakdown belongs to the family oftion, J. Pharm. Sci. 70 (1981) 466–467.

carboxylesterases. Comparison of the carboxylester- [7] Y.W. Chien, K.S.E. Su, S.F. Chang, Nasal Systemic Drugases activity in different regions of the respiratory Delivery, Ch. 1, Marcel-Dekker, New York, 1989.tract revealed that the nasal mucosa contained the [8] Y.W. Chien, S.F. Chang, Intranasal drug delivery for sys-

temic medication, Crit. Rev. Ther. Drug Carrier Syst. 4richest carboxylesterase, with the order being(1987) 67.nasal . pulmonary parenchymal . tracheal. This en-

[9] Y.W. Chien, Transnasal Systemic Medications, Ch. 1,zyme localization pattern certainly causes pre- Elsevier, New York, 1985.systemic breakdown of ester prodrugs even before [10] R.E. Gibson, L.S. Olanoff, Physicochemical determinants ofany transcellular partitioning can occur. In conclu- nasal drug absorption, J. Control. Release 6 (1987) 361–366.

[11] E.B. Roche, in: Design of Biopharmaceutical Propertiession, it can be stated that if the carboxylesteraseThrough Prodrugs and Analogs, American Pharmaceuticalactivity in the mucus and plasma membrane of theAssociation, Washington, DC, 1977, pp. 136–227.

nasal tissues can be circumvented by adequate and [12] M.A. Sarkar, Drug metabolism in the nasal mucosa, Pharm.proper prodrug design, such an approach may be Res. 9 (1992) 1–9.invaluable for both nasal and other non-invasive [13] V.H.L. Lee, A. Yamamoto, Penetration and enzymatic bar-

riers of peptide and protein absorption, Adv. Drug. Del. Rev.transmucosal delivery purposes.4 (1990) 171–207.

[14] A.R. Dahl, The effect of cytochrome P-450 dependentmetabolism and other enzyme activities on olfcation, in: F.L.Margolis, T.V. Getchell (Eds.), Molecular Neurobiology of

7. Conclusion the Olfactory System, Plenum Press, New York, 1988, pp.51–70.

[15] M.S. Bogdanffy, Biotransformation enzymes in the rodentWhile our knowledge of drug delivery has vastlynasal mucosa: the value of a histochemical approach, En-

improved over the years and we have assimilated a viron. Health Perspect. 85 (1990) 177–186.wealth of information on design of prodrug deriva- [16] M.S. Bogdanffy, H.W. Randall, K.T. Morgan, Histochemicaltives for various functional groups, more work needs localization of aldehyde dehydrogenase in the respiratory

tract of the Fisher-344 rat, Toxicol. Appl. Pharmacol. 82to be done to rationally utilize this information base(1985) 560–563.in better design of prodrugs for nasal drug delivery.

[17] M.S. Bogdanffy, H.W. Randall, K.T. Morgan, BiochemicalThis bioreversible derivatization technique is readily quantitation and hisotchemical localization of carboxylester-feasible to obtain derivatives with desired lipophilic- ase in the nasal passages of the Fischer-344 rat and B6C3F1ity and in certain instances metabolic stability. Ester- mouse, Toxicol. Appl. Pharmacol. 88 (1987) 183–194.

[18] M.S. Bogdanffy, C.R. Kee, C.A. Hinchman, B.A. Trela,type prodrug design may prove useful in enhancingMetabolism of dibasic esters by rat nasal mucosal carbox-nasal drug uptake. It can be stated that prodrugs withylesterase, Drug Metab. Dispos. 19 (1991) 124–129.

branched aliphatic side chains should be investigated [19] J.A. Bond, Some biotransformation enzymes responsible forto overcome the issues related to hydrolysis of the polycylic hydrocarbon metabolism in rat nasal turbinates:ester bond prior to absorption. Effects on enzymes of in vitro modifiers and intraperitoneal


and inhalation exposure of rats to inducing agents, Cancer [38] C.H. Huang, Ph.D. Thesis, Univ. of Kentucky, 1983.Res. 43 (1983) 4805–4811. [39] D. Barlow, S. Takashi, The design of peptide analogues for

[20] P.G. Gervasi, V. Longo, F. Ursino, G. Panattoni, Drug improved absorption, J. Control. Release 29 (1994) 283–Metabolizing enzymes on respiratory mucosa of humans, in: 291.I. Schuster (Ed.), Cytochrome P-450: Biochemistry and [40] G.J. Rasmussen, H. Bundgaard, Prodrugs of peptides. 15.Biophysics, Taylor & Francis, New York, 1989, p. 97. 4-Imidazolidinone prodrug derivatives of enkephalins to

[21] J.A. Bond, J.R. Harkema, V.I. Russel, Regional distribution prevent aminopeptidase-catalyzed metabolism in plasma andof xenobiotic metabolizing enzymes in respiratory airways of absorptive mucosae, Int. J. Pharm. 76 (1991) 113–122.dogs, Drug Metab. Dispos. 16 (1988) 116–124. [41] J.K. McDonald, A.J. Barret, Mammalian Proteases: A Glos-

[22] W.B. Jakoby, B. Ketterer, B. Mannervik, Glutathione trans- sary and Bibliography, Exopeptidases, vol. 2, Academicferases: Nomenclature, Biochem. Pharmacol. 33 (1984) Press, NY, 1986.2539–2540.

[42] F.W. Okumu, G.M. Pauletti, D.G. Vander Velde, T.J. Siahaan,[23] A. Aceto, C. Di Ilio, S. Angelucci, V. Longo, P.G. Gervasi,

R.T. Borchardt, Pharm. Res. 12 (1995) S–302.G. Federici, Glutathione transferases in humans nasal mu-

[43] G.M. Pauletti, S. Gangawar, F.W. Okumu, T.J. Siahaan, V.J.cosa, Arch. Toxicol. 63 (1989) 427–431.Stella, R.T. Borchardt, Esterase-sensitive cyclic prodrugs of[24] S.D. Kashi, V.H.L. Lee, Enkephalin hydrolysis in homoge-peptides: evaluation of an acyloxyalkoxy promoiety in anates of various absorptive mucosae of the albino rabbit:model hexapeptide, Pharm. Res. 13(11) (1996) 1615–1623.Similarities in rates and involvment of aminopeptidases, Life

[44] S. Gangawar, S.D.S. Jois, T.J. Siahaan, D.G. Vandervelde,Sci. 38 (1986) 2019–2028.V.J. Stella, R.T. Borchardt, The effect of conformation on the[25] M.A. Hussain, C.A. Koval, A.B. Shenvi, B.J. Aungst,membrane permeability of an acyloxyalkoxy-linked cyclicRecovery of rat nasal mucosa from the effects of amino-prodrugs of a model hexapeptide, Pharm. Res. (1996) 1657–peptidase inhibitors, J. Pharm. Sci. 79 (1990) 398–400.1662.[26] J.A. Faraj, M.A. Hussain, Y. Aramaki, K. Iseki, M.

[45] K.S.E. Su, K.M. Campanale, Nasal drug delivery systems:Kagoshima, L.W. Dittert, Mechanism of nasal absorption ofrequirements, developments and evaluates, in: Y.W. Chiendrugs. III: Nasal absorption of leucine enkephalin, J. Pharm.(Ed.), Transnasal Systemic Medications, Elsevier, Amster-Sci. 79 (1990) 698–702.dam, 1985, pp. 139–159.[27] C.H. Huang, R. Kimura, R. Bawarshi-Nassar, A. Hussain,

[46] S.M. Harding, S. Heath, Intranasal steroid aerosol in peren-Mechanism of nasal absorption of drugs. I: Physicochemicalnial rhinitis: Comparison with an antihistamine compound,parameters influencing the rate of in situ nasal absorption ofClin. Allergy 6 (1976) 369.drugs in rats, J. Pharm. Sci. 74 (1985) 608–611.

[47] D. McCleve, J. Goldstein, S. Silver, Corticosteroid injections[28] C.H. Huang, R. Kimura, R. Bawarshi-Nassar, A. Hussain,of the nasal turbinates: Past experience and precautions,Mechanism of nasal absorption of drugs. II: Absorption ofOtolaryngology 86 (1978) 851.L-tyrosine and the effect of structural modification on its

[48] T.C.A. Kumar, G.F.X. David, B. Umberkoman, K.D. Saini,absorption, J. Pharm. Sci. 74 (1985) 1298–1301.Uptake of radioactivity by body fluids and tissues in tissues[29] S. Muranishi, Absorption enhancers, Crit. Rev. Ther. Drugin rhesus monkeys after intravenous injection or intranasalCarrier Sys. 7 (1990) 1–33.spray of tritium-labelled oestradiol and progesterone, Curr.[30] A.A. Hussain, R. Bawarshi-Nassar, C.H. Huang, Physico-Sci. 43 (1974) 435–439.chemical considerations in intranasal drug administrations,

[49] L. Ohman, R. Hahnenberger, E.D.B. Hohansson, 17b-Es-in: Y.W. Chien (Ed.), Transnasal Systemic Medications,tradiol levels in blood and cerebrospinal fluid after ocularElsevier, Amsterdam, 1985, pp. 121–137.and nasal administration in women and female rhesus[31] A. Helenius, D.R. Mccaslin, E. Fries, C. Tanford, Propertiesmonkeys (Macaca mulatta), Contraception 22 (1980) 349.of detergents, Methods Enzymol. 56 (1979) 734.

[50] L.A. Rigg, B. Milanes, B.Villanueva, S.S.C. Yen, Efficacy of[32] D. Duchene, G. Ponchel, Nasal administration: A tool forintravaginal and intranasal adminstration of micronized 17b-tomorrow’s systemic administration of drugs, Drug. Dev.estradiol, J. Clin. Endocrinol. Metab. 45 (1977) 1261–1264.Ind. Pharm. 19 (1993) 101–122.

[51] G.F.X. David, C.P. Puri, T.C.A. Kumar, Bioavailability of[33] V. Stella, in: T. Higuchi, V. Stella (Eds.), Prodrugs as Novelprogesterone enhanced by intranasal spraying, Experientia 37Drug Delivery Systems American Chemical Society,(1981) 533–534.Washington, DC, 1975, pp. 1–115.

[52] Y.W. Chien, D.C. Corbo, Y. Huang, Nasal controlled delivery[34] A. Albert, Nature 182 (1958) 421–430.and pharmacokinetics of progestational steroids and effect of[35] S.M. Kupchan, A.F. Casy, J.V. Swintosky, J. Pharm. Sci. 54penetrant hydrophilicity, Proc. Int. Symp. Control. Release(1965) 514–518.Bioact. Mater. 15 (1988) 191.[36] H. Bundgaard, Design of prodrugs: bioreversible derivatives

[53] D.G. Shand, E.M. Nuckolls, J.A. Oates, Plasma propranololfor various functional groups and chemical entities, in: H.levels in adults, Clin. Pharmacol. Ther. 11 (1970) 112–120.Bundgaard (Ed.), Design of Prodrugs, Elsevier, New York,

[54] A.A. Hussain, T. Foster, S. Hirai, T. Kashihara, R.1985, pp. 1–92.Batenhorst, M. Jones, Nasal absorption of propanolol in[37] H. Bundgaard, The utility of the prodrug approach tohumans, J. Pharm. Sci. 69 (1980) 1240.improve peptide absorption, J. Control. Release 21 (1992)

63–72. [55] G.S.M.J.E. Duchateau, J. Zuidema, W.M. Albers, F.W.H.M.


Merkus, Nasal absorption of alprenolol and metoprolol, Int. Systemic Medications: Fundamentals, Developmental Con-J. Pharm. 34 (1986) 131–136. cepts and Biomedical Assessments Elsevier, Amsterdam,

[56] G.S.M.J.E. Duchateau, J. Zuidema, F.W.H.M. Merkus, Bio- 1985, pp. 2–99.availability of propanolol after oral, sublingual, and intranas- [73] P. Tengamnuay, A.K. Mitra, Transport of tyrosine andal administration, Pharm. Res. 3 (1986) 108–111. phenylalanine across the rat nasal mucosa, Life Sci. 43

[57] A.A. Hussain, R. Kimura, C.H. Huang, T. Kashihara, Nasal (1988) 585–593.absorption of naloxone and buprenorphine in rats, Int. J. [74] D.S. Lovelace, Z. Shao, A.K. Mitra, Transport of L-Pharm. 21 (1984) 233–237. tryptophan across the rat nasal mucosa, J. Pharm. Sci. 82

[58] Y. Kaneo, Absorption from the nasal mucous membrane: I. (1993) 251–252.Nasal absorption of hydralazine in rats, Acta Pharm. Suec. [75] Z. Shao, R. Krishnamoorthy, A.K. Mitra, Cyclodextrins as20 (1983) 379–388. nasal absorption promoters of insulin: Mechanistic evalua-

[59] S. Hirai, T. Yashiki, H. Mima, Mechanisms for the enhance- tions, Pharm. Res. 9 (1992) 1157–1163.ment of the nasal absorption of insulin by surfactants, Int. J. [76] P. Tengamnuay, A.K. Mitra, Bile salt-fatty acid mixedPharm. 9 (1981) 173–184. micelles as nasal absorption promoters of peptides. I. Effects

[60] A.B. Hill, C.J. Bowley, M.L. Nahrwold, P.R. Knight, M.M. of ionic strength, adjuvant composition, and lipid structure2Kirsh, J.K. Denlinger, Intranasal administration of nitro- on the nasal absorption of [D-Arg ]Kyotorphin, Pharm. Res.

glycerin, Anesthesiology 54 (1981) 346–348. 7 (1990) 127–133.[61] A. Barach, B. Garthwaite, F.F. Anderson, An apparatus for [77] P. Tengamnuay, A.K. Mitra, Bile salt-fatty acid mixed

the introduction of penicillin aerosol into the nasal accessory micelles as nasal absorption promoters of peptides. II. Insinuses with a case report of a patient with chronic sinusitis, vivo nasal absorption of insulin in rats and effects of mixedAnn. Int. Med. 24 (1946) 97. micelles on the morphological integrity of the nasal mucosa,

[62] S. Hirai, T. Yashiki, T. Matsuzawa, H. Mima, Absorption of Pharm. Res. 7 (1990) 370–375.drugs from the nasal mucosa of rat, Int. J. Pharm. 7 (1981) [78] K.S.E. Su, K.M. Campanale, C.L. Gries, Nasal drug delivery317–325. system of a quarternary ammonium compound: Clofilium

[63] A. Rubinstein, Intranasal administration of gentamicin in tosylate, J. Pharm. Sci. 73 (1984) 1251–1254.human subjects, Antimicrob. Agents Chemother. 23 (1983) [79] P. Larochelle, P. DuSouich, E. Bolte, J. Lelorier, R. Goyer,778–779. Tixocortol pivalate, a corticosteroid with no systemic

[64] R.A. Bucknall, Why aren’t antivirals effective when adminis- glucocorticoid effect after oral, intrarectal, and intranasaltered intranasally? in: J.S. Oxford and J.D. Williams (Eds.), application, Clin. Pharmacol. Ther. 33 (1982) 343–350.Chemotherapy and Control of Influenza, Academic Press, [80] Z. Shao, A.K. Mitra, Nasal membrane and intracellularNew York, 1976, pp. 77–80. protein and enzyme release by bile salts and bile salt-fatty

[65] R.A. Levandowski, C.T. Pachucki, M. Rubenis, G.G. Jack- acid mixed micelles: Correlation with facilitated drug trans-son, Topical enviroxime against rhinovirus infection, Anti- port, Pharm. Res. 9 (1992) 1184–1189.microb. Agents Chemother. 22 (1982) 1004–1007. [81] G.-B. Park, Z. Shao, A.K. Mitra, Acyclovir permeation

[66] N. Schaffer, E. Seidmon, The intranasal use of enhancement across intestinal and nasal mucosae by bileprophenpyridamine maleate and chloroprophenpyridamine salt-acylcarnitine mixed micelles, Pharm. Res. 9 (1992)maleate in allergic rhinitis, Ann. Allergy 10 (1952) 194. 1262–1267.

[67] L.H. Hamilton, Effect of topical decongestants nasal airway [82] Z. Shao, Ph.D. Thesis, Purdue University, West Lafayette,resistance, Curr. Ther. Res. 24 (1978) 261. IN, 1994.

[68] P.I. Jatlow, D.N. Bailey, Gas chromatographic analysis of [83] Z. Shao, G.-B. Park, R. Krishnamoorthy, A.K. Mitra, Thecocaine in human plasma with use of a nitrogen detector, physicochemical properties, plasma enzymatic hydrolysis,Clin. Chem. 21 (1975) 1918–1921. and nasal absorption of acyclovir and its 29-ester prodrugs,

[69] M. Unger, A new method for cocainizing the nasal mucosa, Pharm. Res. 11 (1994) 237–242.Eye Ear Nose Throat Month. 43 (1964) 60. [84] Z. Shao, A.K. Mitra, Bile salt-fatty acid mixed micelles as

[70] P. Wilkinson, C.V. Dyke, P. Jatlow, P. Barash, R. Byck, nasal absorption promoters. III. Effects of nasal transport andIntranasal and oral cocaine kinetics, Clin. Pharmacol. Ther. enzymatic degradation of acylovir prodrugs, Pharm. Res. 1127 (1980) 386–394. (1994) 243–250.

[71] A.N. Fisher, K. Brown, S.S. Davis, G.D. Parr, D.A. Smith, [85] Z. Shao, A.J. Hoffman, A.K. Mitra, Biodegradation charac-The nasal absorption of sodium cromoglycate in the albino teristics of acyclovir 29-esters by respiratory carboxylester-rat, J. Pharm. Pharmacol. 37 (1985) 38–41. ases: Implications in prodrug design for intranasal and

[72] Y.W. Chien, S.F. Chang, Historic development of transnasal pulmonary drug delivery, Int. J. Pharm. 112 (1994) 181–systemic medications, in: Y.W. Chien (Ed.), Transnasal 190.

Prodrugs for nasal drug delivery

Documents

Transcript of Prodrugs for nasal drug delivery