Indian Journal of Experimental Biology Vol. 37, January 1999, pp. 6-16

Review Article

Recent trends in drug delivery systems: Intranasal drug delivery

Varsha Agarwal & B. Mishra

Department of Pharmaceutics, Insti tute of Technology, Banaras Hindu University, Varanasi 221005, India

Nasal route of drug delivery is commonly known for treatment of local ailments like-cold, cough, rhinitis etc. Recently, efforts have been made to deliver various drugs, specially peptides and proteins, through nasal route for systemic use; utilizing the principles and concepts of rate controlled drug deliv­ery and various polymers and absorption promoters. Considering the large number of problems associ­ated with oral, parenteral, rectal and other routes of drug administration and gradual increase in interest of pharmaceutical scientists towards exploring the possibilities of intranasal delivery of various drugs, this article aims at giving an insight into nasal cavity, consideration of factors affecting and strategies to improve drug absorption through nasal route, pharmaceutical dosage ' forms and delivery systeInf ,vith examples of some peptides for intra nasal delivery, its advantages and limitations.

Drugs are administered traditionally by oral· and parenteral routes for systemic dilivery. The gas­trointestinal tract (GIT) is the major route of drug entry to the systemic circulation. However, for some drugs this route presents problems. The gas­trointestinal tract presents a hosti le environment; it contains enzymes, a wide range of pH conditions and varies in its composition depending upon the presence or absence of food. Those drugs which are susceptible to either acid hydrolysis or exten­sive metabolism in the liver may exhibit poor bio­availability when administered via this route. Drugs administered via the parenteral route gain access to the systemic circulation directly and pro­duce maximum plasma levels but this route is as­sociated with pain and discomfort and can only be gi ven by medical personnel. Parenteral formula­tions need to be sterilised and this increases the cost. In addition certain health risks are associated with this route, e.g. , psychological distress, occas­sional allergies and hypertrophy or atrophy of the subcutaneous f~t at the injection site specially on chronic administration.

In an attempt to circumvent these problems, al­ternative routes of drug administration are being investigated. Transdermal , rectal, buccal and nasal routes bypass hepatic first-pass metabolism and offer alternative routes for the systemic delivery of drugs. However, transdermal route does not provide rapid blood levels and is limited to controlled de­livery of potent lipophillic drugs. The rectal route

suffers from variable patient acceptance and de­pending upon the site of absorption the drug may be subjected to hepatic first-pass metabolism. Buc­cal and sublingual routes of drug administration are of much interest, but sometimes pose incon­veniences during speaking, eating and drinking.

Hence, the nasal route holds potential for ad­ministration of various drugs with avoidance of first-pass metabolism and the better bioavailability and therapeutic profiles. The nasal route for drugs administration has received the attention of man­kind since ancient times. Nasal therapy (Nasaya karma) is a recognized form of treatment in the Indian system of medicine. The intranasal applica­tion of tobacco snuff, cocaine and various hallu­cinogenic and psychotropic agents has been known for a long time. It is therefore surprising that only in the past decade this route attracted much atten­tion for systemic medication . The results till date indicate that the nasal route of drug delivery is considered to be the most promising due to its fo llowing potential advantages

(1 ) Avoidance of drug degradation in the lumi­nal fluid of the GI tract.

(2) Avoidance of hepatic first-pass metabol ism in the liver or gut wall.

(3) Easily accessible. (4) Rapid absorption and fast onset of action . (5) Suitable for administration for long term

therapy.

AGARWAL & MISHRA: INTRA NASAL DRUG DELIVERY SYSTEM 7

(6) Improved compliance, particularly of drugs with short half li fe.

(7) Good bioavailability of small drug mole­cules.

(8) Obtaining therapeutic level ~ 0 those drugs that are active in small doses.

(9) No requirement of formulations in complex or expensive single dose delivery system.

(10) The absorption rate profiles of many non­protein drugs administered nasally are similar to that for intravenous administration.

The advances in biotechnology have made available a large number of proteins and peptides as future therapeutic drugs . Interest in the drug delivery 01 pep tides and proteins through nasal route has recently been growing. Intranasal ad­ministration of various peptide agents including luteinizing hormone releasing hormone (LHRH), vasopressin, oxytocin, enkephalins, growth hor­mone releasing hormone (GHRH), adrenocortico­tropic hormone, thymopentin, thyrotrop in releasing hormone (TRH) , secretin, calcitonin and insulin have been investigated in the past. The vasopressin analogs and oxytocin are examples of intranasal products cuncntly available in the market.

Nasal cavityl The total surface area of the nasal cavity is ap­

proximately 150-1 60 cmz with a total volume of 15m!' The nasal cavities are lined with mucosa which is 2-4 mm thick. The epithelium contains cilliary cells characterized by an automatic unidi ­rectional backward flow of mucus and trapped particles towards the pharynx with a flow of ap­proximately 5-6 mm/min. Beneath epithelium are three layers of mucosa characterized by a rich vas­cular and lymphatic network. The rich vasculature and numerous microvill i structures in the nasal ti ssue make it an absorption site wi th great poten­tial [or a vari ety of drugs. Therefore the intTanasal route shows a greater promise for incr{.asing thet'a­peutic applic2bili ty2

Factors influe nci ng nasal d rug absorption (A) Physicuchcmicai

(a) MO!cL""il.lr !.ize and slructure--Na:,ai ab­sorption decreases sigill ficantly when mok cular wei ght of dru g is great~r than J 000 Daltons. A re­verse relatioliship ha3 been dernonstra t~d between

molecular size and the nasal absorption in rats and rabbits3

-6 . These studies support the idea that water soluble, high molecular weight drugs cross the na­sal mucosa mainly by passive diffusion through the aqueous pores (i .e., tight junctions). Supporting evidence is given by McMartin et aC who looked for relationships between published value for nasal absorption of a large variety of peptides and pro­teins and their physico chemical properties. The hest correlation exists between molecular size and extent of nasal absorption, consistent with diffu­sion through intercel1ular pores as a major mecha­nism of transport for peptides and proteins. Data on active transport of peptides by endocytosis are scarce. It is interesting to note that earlier reports on relationship between molecular weight and na­sal absorption of peptides and proteins are very contradictory. Some authors7

-9 claim an inverse

relationship between molecular size and nasal bio­availability whereas others 1o

.11 state that such rela­

tionship does not exist. Apparently, the nasal ab­sorption of peptides and proteins is rather compli­cated due to variously charged and variously shaped molecules. The effect of molecular weight on absorption is related to the effective size of the molecules. Cyclic peptides are absorbed much better than linear ones.

(b) Hydrophilicity/Upophilicity--The effect of drug hydrophilicity on absorption rate has been clearly shown by Carbo et al.12 using progesterone as a model drug. The systemic bioavailability was decreased with increasing hydrophilicity of the drug_

(B) Biochemical alld physiological The nasal mucosa is by itself an enzymatic bar­

rier to nasally admini tered drug consisting of several different proteolytic/hydrojytic enzyrnes lJ

-16

•

The enzymes present are both oxidative (e .g., cy­tochrome pASO, alcehyde de hydrogenase, car­hoxyesterase, carbonic anhydrase) and conj ugative (e.g. , glucuronyl sulphate and o-iuia th ione transfer­asc.) enzymes. Cytochrome p.-4 -0 activity in the olfactory region of the nasa l cavity is even higher {han in the liver. The enzymatic act! vities clearing peptides and pr reins are exo- and endopeptidases (e.g., aminopept!oascs, carboxyp~:iJases , tryps!!) ; ke acti vities, cathepsin), whi ch arc present at the su~face or the nasal mucosa or Within epithei al

8 INDlAN 1. EXP. BIOL., JANUARY 1999

cells. Among these enzymes, aminopeptidase ac­tivity is predominant. The nasal and ileal mucosal homogenates from the albino rabbit showed simi­lar aminopeptidase activities when measured at a protein concentration of approximately 10 mg/mI1 7. The enzymatic barrier characteristics of the nasal mucosa create "a pseudo-first-pass­effect" which may hamper nasal drug absorption l6

.

(C) Nasal mucociliary clearance

It is an important physiological defence mecha­nism of the nose to protect the body against the inhalation of foreign substances. Inhaled/instilled particles are cleared from the nasal cavity by mu­cociliary clearance. Thus every pharmaceutical system intended for intranasal use will interact with the nasal clearance mechanism. Ciliostasis prevents the defensive barrier from functioning properly . Consequently, as ciliary beating is the most important parameter in nasal mucociliary clearance, it should not be affected by nasal medi­cation and additives such as preservatives and ab­sorption enhancers. Furthermore, the rheological properties of the mucus layer can change after contact with pharmaceutical formulations . This will certainly affect the clearance and exposure of drugs to the mucosa. To study the action of drugs, additives and pharmaceutical dosage forms on mu­cocilary clearance, measurement of mucus trans­port time (MIT) and cilliary beat frequency (CBF) are currently used.

(D) Common cold or pathological conditions

The common cold or any pathological condi­tions involving mucocilliary dysfunction can greatly affect the rate of nasal clearance and sub­sequently the therapeutic efficacy of drug admin­istered intranasally. Nasal obstruction as a result of extensive nasal polyposis would reduce the capac­ity of nasal absorption 18. In addition, atrophic rhi­niti s or severe vasomotor rhinitis could also reduce the usefulness of the nose to absorb a drug. In some people, an excessive response of the secre­tory system to some irritants could drain away whatever is introduced prior to its absorption. Such tendency may exist in persons with severe nasal aIlergies. Nevertheless, it has been shown that the common cold and rhinitis do not decrease the bio­a vailability of buserelin 19 and desmopressin20

.

(E) Pharmaceutical

(a) Formulation (pH and osmolarity)-The formulation plays an important role in the nasal absorption of drugs as it does in case of other routes of administration. The influence of pH and osmolarity on the nasal absorption of secretin are studied in rats21 . The study indicated that the ab­sorption of secretin increased linearly as pH de­creased from 7.0 to 2.94. Its bioavailability was also affected by sodium chloride concentration in the formulation. The maximum absorption was obtained with a hyperosmolar saline solution of 0.462M.

(b) Droplet size-The mean flow rate of the mucociliary system of the normal nose ;:; about 5 mmlmin. up to 20 mmlmin22 or administered drugs are cleared from the nasal cavity wi thin 15 to 20 min, depending on the particle size of the materials and the site of deposition. The particles with an aerodynamic size above 10-20 /lm are :ill depos­ited in the nasal cavity, whereas particles smaller than 1 /lm pass with inspired air into the lungs.

(c) Site of deposition-However, the degree of absorption also depends on the site of deposition of nasally administered substances which depends on the delivery system and the technique of admini­stration. For instance, the deposition and clearance of nasal sprays and nasal drops of Tc-99m labeled human serum albumin were studied23 in humans using gamma scintigraphy. The nasal spray was deposited mainly in the anterior part of the nose whereas the nasal drops dispersed more exten­sively in the nasal cavity. The solution deposited from the nasal drops cleared more rapidly than from the nasal spray.

(d) Delivery .system-"':v'arious delivery systems such as nasal sprays, nasal drops, cotton pledget, insufflator, nasal insert and nasal jelly are cur­rently used for administration of drugs through the nasal cavity. TI1e different delivery efficiency of these systems affect the 'lite of deposition and the degree of absorption.

(e) Drug distribution-Drug distribution in the nasal cavity is another important fac tor in the nasal absorption of drugs. This in tum is affected by several factors such as :

(i) Area of the nasal mucus membrane ex­posed--An ointment containing 40mg progester-

AGARWAL & MISHRA: INTRANASAL DRUG DELIVERY SYSTEM 9

one when applied into both the nostrils of a woman showed increased bioavailability compared to that obtained after administration to just one nostri1.24

(ii) Volume of solution applied-Application of a large volume of a solution from the nasal drop bottle gives a good distribution over the nasal cav­ity, whereas samll volume gives unsatisfactory results .

(iii) Types of nasal delivery systems-Various nasal delivery systems such as drop bottles, plastic bottle nebuliser, atomised pump and metered dose pressurised aerosol showed significant differences in drug distribution in human nose25.26. The studf7 has shown that the relative bioavailability and biological response to nasal desmopressin was better with nasal spray than with nasal drops be­cause of better distribution . For a pressurised aero­sol system, dosage should be delivered twice in each nostril, i.e., one puff in the upper direction and one puff in the lower direction, in order to yield a reasonably good distribution of drug.

Strategies to improve nasal absorption Though the nasal absorption of small non­

peptide drugs is considerably good, the nasal bio­availability of peptide and protein drugs is low. The low nasal absorption may be due to poor membrane permeability to larger molecules or lack of lipophilicity or metabolic degradation by ami­nopeptidase present in the nasal mucosa. To over­come these problems several strategies have been tried to enhance the nasal absorption of peptides and protein drugs to improve their bioavailability.

(1) Synthesis of stabilised and more /ipophillic analogues

Many potent peptide analogues have been syn­thesized which possess high lipophilicity and in­creased stability to enzymatic degradation. This approach has led to the development of many na­sally active peptides for example, metkephamid28, antidiuretic drug desmopressin27

•29, LHRH agonist

buserelin8.3O, leuprolide31.32 and nafarelin33.34. The

effect of these nasally administered LHRH ana­logues on the induction of ovulation is increased to 50-200 times in comparison to the parent com­pound LHRH, but their nasal bioavailability re­mained very low (2-3%t The discrepancy found between nasal bioavailability and induced biologi-

cal activities can probably be attributed to high affinity of the pituitary receptors for these LHRH agonists.

(2) Peptidase and protease inhibitors The nasal epithelial tissue contains substantial

amounts of peptidases and proteases. These en­zymes are able to degrade peptides and proteins like enkephalins, insulin and proinsulin. The pre­dominant enzyme present is aminopeptidase.

The aminopeptidase inhibitors such as bacitra­cin, bestatin and amastatin have been found to promote the nasal absorption of LHRH peptides35, salmon calcitonin36, leucine enkephalin37 and hu­man growth hormone38 in rats . A new aminopepti­dase inhibitor, boroleucine has also been found37 to remarkably enhance the nasal absorption of leucine enkephalin in rats. The intranasal use of a-aminoboronic acid derivatives for the stabiliza­tion of externally administered leucine-enkephalin as a model peptide was studied in situ in rats . These compounds were found to greatly inhibit the degradation of leucine enkephalin in the nasal per­fusate. Enzyme inhibition was greater with boro­leucine and borovaline than with boroalanine de­rivatives. The boroleucine derivatives was more than 100 times more effective in enzyme inhibition than bestatin and more than 1000 times more ef­fective than puromycin.

(3) Absorption enhancers Absorption enhancers have most frequently

been used to improve the bioavailability of intra­nasally administered peptides and proteins39. Vari­ous types of absorption enhancers along with ex­amples are presented below:

Class

(a) Surfactants

(b) Glycosides (c) Bile Salts

Compounds

Polyoxyethylene-9-lauryl ~ther (Iaureth-9) Saponins Dihydroxy Salts Sodium deoxycholate Sodium glycodeoxycholate Sodium taurodeoxycholate Trihydroxy Salts Sodium cholate Sodium glycocholate Sodium taurocholate

10 INDIAN J.exp; BIOL., J~UARY 1999

(d) Chelators

(e) Fatty Acid Salts

(f) Fusidic Acid Derivatives

(g) Phospholipids

(h) Glycyrrhetinic Acid Derivatives

(i) Cyclodextrins

(j) Glycols

(k) Cyclic Peptide Antibiotics (1) Preservatives

(m) Carboxilic Acids

Salicylates Ethylenediamine tetraacetic acid (EDTA) Citrates Sodium caprylate Sodium caprate Sodium laurate Sodim taurodihydrofusidate (STDHF) Sodium dihydro fusidate Lysophosphatidyl choline Palmitoyl lysophosphatidyl choline Stearoyl lysophosphatidyl choline Didecanoyl phosphatidyl choline Sodium glycyrrhetinate

Dipotassium glycyrrhizinate Disodium salt of carbenox­olone a and 13 cyclodextrins Cyclodextrin derivatives (DMI3CD) n-Glycofurals n-Ethylene Glycols Bacitracin

Methyl-p-hydroxy benzoate Propyl-p-hydroxy benzoate Chlorobutol Chlorocresol Benzal konium chloride Ascorbic acids

Amino acids (n) O-acyl camitine Octanoyl camitine derivatives

Lauryl camitine Palmitoyl camitine

Mechanism of action of absorption enhancers

(1) Increase in membrane fluidity either by cre­ating disorder in the phospholipid domain in the membrane or by facilitating the leaching of drugs from the membrane.

(2) Decrease in viscosity of mucus layer thereby increasing membrane permeability.

(3) Inhibit proteolytic enzymes at the absorp­tion site.

(4) Transient loosening of the tight junctions between certain epithelial cells.

(5) Increase paracellular or transcellular trans-port.

(6) Dissociate protein aggregation. (7) Initiate membrane pore formation. (8) Increase nasal blood flow, thereby ralsmg

the concentration gradient across the nasal mucosa. Starch microspheres have also been shown to

act efficiently as absorption enhancers4o. Insulin and starch microspheres given as a powder nasally to rats rapidly decreased the blood glucose leveI41

•42

•

Hermens and coworkers43 have found that all enhancers have a ciliostatic/toxic effect. However, all the data available today indicate that sodium taurodihydrofusidate (STDHF) is one of the most promising enhancers system.

The most important drawback for the use of chemical nasal enhancers is the possibility of toxic side effects. The chronic administration causes irreversible damages to the nasal mUGOsa. There is presently a need for good nasal absorption en­hancers with low or free of any side effects.

Intranasal administration of peptides

The nasal administration of peptide hormone has been attempted previously notably with insulin in the early 1920s44.45

• The nasal administration of peptides has sinc:e become routine for peptides like vasopressin and its analogues dA VP (for the man­agement of diabetes inspidus.), LHRH (for the management of cryptorchidism) and its highly ac­tive analogues (buserelin, leuprolide, LHRHt, and nafarelin, for the management of prostatic carci­noma, mammary carcinoma, uterine leiomyoma, endometriosis, precocious puberty and for contra­ception) and oxytocin (for labour induction)44.9. All these peptides consist of either 10 amino acids or less and therefore possess relatively good perme­ability across nasal mucosal membrane.

Intranasal administration of some common pep­tides with their therapeutic benefits are presented below:

Calcitonin-Calcitonin, a polypeptide hormone, lowers blood calcium concentration and inhibits

AGARWAl:. ~MlSHRA: INTRi\NASALDRUG DELIVERY SYSTEM 11

bone sorption. It is currently used for the treatment of several bone diseases such as hypercalcemia, postmenopausal osteoporosis and pagets disease. Calcitonin is presently given either as subcutane­ous (s.c.) or intramuscular (i .m.) injection daily or on alternate days for prolonged periods. Nasal ad­ministration of calcitonin has been examined46-48 clinically with different dosage forms and formu­lations.

A two year study on efficacy and safety of nasal calcitonin suggests that calcitonin nasal spray has a significant bone protective action49. Clinical stud­ies have demonstrated that nasal delivery of calci­tonin is both convenient and reliable.

Human calcitonin is absorbed through the nasal mucosa without use of surfactants46

• The bioavail­ability is 111 4 times to that of s.c. calcitonin. How­ever, the presence of surfactants such as TDHF and sodium glycocholate enhanced the bioavailability 6-7 times when compared to formulations with no surfactants5o.

Insulin--Insulin is , a protein hormone with a molecular weight of about 5800. The treatment of diabetic patients with insulin requires daily subcu­taneous injections. For both type I and II diabetes, these insulin injections cause local discomfort and inconvenience. More importantly, the subcutane­ous insulin therapy is limited by the delayed onset time and time to reach miximum plasma concen­tration (Tlllax). Furthermore, the injected insulin can not be adjusted to changing requirements during . excercise or meals and therefore can cause large inter and intra subject variability which can result hyper or hypoglycemia.

To date it has been clearly shown that nasal de­livery of insulin results in rapid peaks of circulat­ing insulin which controls meal induced hypergly­cemia. The rapid onset of insulin action simulates the release of insulin by the normal pancreas, at least in timing. In contrast, the delay in absorption from the subcutaneous site may permit hypergly­cemia to occur. However, only the i.v. and i.p. in­jections of insulin administered at meal time con­trols the meal induced glycemic excursion. As a result, nasal delivery has been advocated as a po­tentially useful alternative to s.c. insulin for meal time insulin therapy.

The modern era of intranasal (i .n.) insulin ad­ministration began in the early 1980s. Insulin was

only moderately absorbed when the pH of the so­lution was lowered to about 3.5 or when surfac­tants like bile salts, PEG, detergents, saponin, polyethers usually at 1 % w/v concentration were used in the formulations.

Using intranasal drops of soluble insulin (0.9U/kg) with 1 % sodium glycocholate Pontiroli et al. 51 demonstrated a decrease of blood glucose levels and appearance of insulin in blood stream, both in normal subjects and in patients with type-I diabetes. The efficiency was about 1I9 times to that of intravenous insulin. The bioavailability of intranasal insulin can be improved by increasing the sodium glycocholate concentration from 1-4% (Pontiroli et al.)52. Longenecker53 used TDHF as absorption enhancer and found high reproducibility of intranasal insulin. Previous studies have shown that chemically modified cyclodextrins, especially 'he methylated derivatives, are more potent en­hancers of nasal insulin absorption, than the parent cyclodextrins54-56. The absorption enhancement afforded by the methylated cyclodextrins can be attributed primarily to their ability to reduce the barrier function of the nasal mucosa and to protect insulin against proteolysis55 . Shao et al.57 have demonstrated that cyclodextrins inhibit the sel f association of insulin into oligomers thus making insulin more available for insulin absorption.

DS-I is a semisynthetic derivative of QS-21, a natural saponin isolated from the bark of the Quil­laja saponaria Molina tree. It promotes the sys­temic absorption of aminoglycoside antibiotic when used nasally to mice and rats57 and insulin when applied topically to the rat eye or nose even at concentration as low as 0.025%58. No other ab­sorption enhancing agent has been this effective when used at such low concentrations. The hypo­glycemic response was more rapid in onset and more transient than that observed when insulin was injected (s.c.).

The effect of soyabean-derived sterol mixture (SS) and its glucoside mixture (SG) as an enhancer to improve the nasal bioavailability of insulin is reported in rabbits59. SG possesses excellent prop­erties in peanut oil suspension as an enhancer and is superior to the known absorption enhancers.

IlIum et al.60 reported the successful use of a medium molecular weight chitosan to enhance the nasal absorption of insulin in rat and sheep models.

12 INDIAN J. EXP. BIOL., JANUARY 1999

The mechanism of action was suggested to be a combination of bioadhesion and transient widening of the tight junctions in the nasal membrane. Re­cently, a range of chitosans differing in molecular weight and degree of deacetylation, were all shown to enhance the systemic delivery of insulin when administered nasally to rats6 1

• Further, it was shown that the chitosan caused no membrane or cellular damage in rat nasal perfusion model61 and only a transient decrease in mucociliary transport velocity in the frog palate model62

• It is also re­ported63 that hyaluronic acid ester microspheres significantly enhance the intranasal absorption of insulin in sheep .

Glucagon-Glucagon, a peptide hormone is highly effective in counteracting hypoglycemia. Conventionally it is administered intravenously or intramuscularly. Intranasal glucagon is as effective in terms of hyperglycemia as i.v. glucagon and somewhat less effective than i.m. glucagonM

. Hy­perglycemic effect of intranasal glucagon was short lived while intramuscular glucagon, at the usual dose of 1 mg exerted an exaggerated effect which lasted more than 3 hr65

• Intranasal glucagon spray seems a feasible remedy for hypoglycemic cri ses and as a quick form of self medication for emergencies.

Endocrine hormones

Human Growth Hormone (hGH)-A protein hormone, is currently administered s.c. or i.m. to children deficient in growth hormone for treatment of hypopituitary dwarfism. More recently hGH was reported to reverse the biological effects asso­ciated with aging.

The nasal bioavailability of recombinant me­thionyl-human growth hormone (Met-hGH) was found66 to be less than I % as compared to i.v. ad­ministration . However, in presence of absorption enhancer sodium glycocholate, the nasal absorp­tion of Met-hGH was increased to about 7-8%. The nasal absorption of hGH in the presence of lyso­phosphatidyl chlol ine and sodium dihydrofusidate derivati yes was investigated38 in rats , rabbits and sheep and it has been found that these absorption enhancers signifi<;antly improves delivery ofhGH.

Luteinizing Hormone Releasing Hormone (LHRH)-LHRH, a decapeptide secreted in the hypothalamus stimulates the release of gonadotro-

pins, LHRH and follicle stimulating hormone (FSH), from the anterior pituitary. In recent years, potent LHRH agonist analogues have been devel­oped. These analogues suppress gonadotropin re­lease for treatment of endometriosis, prostate car­cinoma and female contraception. These hormones are essentially inactive when administrated orally.

The nasal bioavailability of LHRH was esti­mated to be approximately I % when compared with peak plasma levels of LHRH after i.v. ad­ministration. The treatment of cryptorchidism in young boys requires injections and it is not well tolerated by infants. In some cases, it leads to symptoms of androgenic stimulation which are unwanted in prepubertal children. The nasal ad­ministration of LHRH has been found to be effec­tive with a multiple dosage regimen67

. Although a higher nasal dose is required than the i. v. dose, this route seems a safe and convenient for LHRH ad­ministration. Moreover absorption is not affected by common cold or intercurrent rhinitis . LHRH agonist (buserelin). a synthetic non peptide buserelin acetate is a highly potent agonist of LHRH. In contrast to acute dosing, the long term treatment with the LHRH agonist paradoxically desensitizes the pituitary gonadal 'system, leading to a reversible biochemical castration. "This para­doxical effect is successfully utilized in the treat­ment of hormonally sensitive disorders such as endometriosis, precocious puberty and leio­myoma68

. Because of the low oral bioavailability of buserelin, it is administered via the intranasal route or by s.c. implants or microparticle injec-tions69 . .

The effects of chemically modified cyclodex­trins on the nasal absorption of buserlin, agonist of LHRH were investigated70 in anaesthetised rats . a-cyclodextrins, dimethyl-a-cyclodextrins and dimethyl-!)-cyclodextrins significantly enhanced the rate and extent of nasal bioavailability of buserelin with the efficacy increasing in the order a-cyclodextrin <diinethyl-a-cyclodextrin <di­methyl-l3-cyclodextrin. In particular, DM­!)-cyclodextrin improved the nasal bioavailability of buserelin about four fold , reaching ~60% when compared to i.v. administration. Cyclodextrins protect the buserelin acetate from proteolytic en­zymes by including the aromatic amino acid within their intramolecular cavity. Cyclodextrins are ca-

AGARWAL & MISHRA: INTRANASAL DRUG DELIVERY SYSTEM 13

pable of extracting specific membrane lipids such as cholesterol and phospholipid from the nasal mucosa through rapid and reversible formation of inclusion complexes. This selective solubilisation of the membrane lipids may reduce the barrier function of the nasal epithelium.

Nasal absorption of nafarelin acetate, a potent · LHRH agonist, in rhesus monkeys was found to be rapid and reproducible33. Clinical trials of nasal delivery of nafarelin have shown good efficacy in the treatment of endometriosis and it is currently marketed in the United States.

The resean:;h has also now been initiated on a novel peptide absorption promoting agents which are termed as "physiological modifying agents". These agents have vasoactive properties and exert their action by increasing nasal mucosal blood flow. As a result the concentration of the drug on the basal side of the nasal mucosal membrane will remain low, leading to an increase in effective concentration gradient and thereby augmenting peptide permeation across the mucosal membrane by passive diffusion.

Agents capable of increasing nasal blood flow are histamine71, leukotriene D/2, prostaglandin E73, I)-adrenergic agonists, isoprenaline and terbuta­line74. Also included in this category are agents which promotes the release of endogenous vasoac­tive substances such as histamines, Kinins, prosta­glandins and vasoactive peptides. Carboxymethyl cellulose (CMC), a bioadhesive agent and hista­mine, a vasodilator were used to enhance the intra­nasal absorption of desmopressin, a 9-amino acid v('.sopressin analog in human trials75. The intrana­sal administration of histamine immediately prior to desmopressin significantly increased nasal blood flow response, suppressed urine volume flow for longer duration, and increased urine os­molality, electrolyte and creatinine concentration. The increase in duration of activity was consistent. with increased transnasal absorption of the peptide.

Pharmaceutical formulations

The fourth strategy for improved delivery of peptides. and proteins through nasal route is for­mulation approach. Rapid mucocilliary clearance of drugs from absorption sites in the nasal cavity is responsible for low bioavailability. With the aim to prolong the nasal residence time and improve the

absorption efficiency, remarkable progress has been reported with the formulation approach.

Various dosage forms

The conventional nasal dosage forms are simple solutions meant for local application. These solu­tion dosage forms are effective . in relieving the symptoms of rhinitis and common cold by pro­viding better distribution of the drug than any other dosage form. However, for systemic m~dications a satisfactory pharmacokinetic profile and good bio­availability are essential.

Since solution dosage forms are easily subjected to nasal mucociliary clearance, other dosage forms such as suspensions, powders and inserts are de­veloped to improve the nasal drug absorption into the systemic circulation, e.g., the nasal absorption of human sodium insulin was found76 to be better from suspensions when compared to solution dos­age forms. This might be due to higher drug con­centration on nasal membrane which in turn results in an increased concentration gradient for drug diffusion.

The powder dosage form is prepared by mixing the drug with water-soluble, water-dispersible or water-insoluble polymers. The mixed powder is dissolved and lyophilized and filled in hard gelatin capsule. The powder dosage form can be adminis­tered with an insufflator or other delivery devices.

Gel formulations-The nasal absorption of ni­fedipine from various gel formulations was inves­tigated in rats77

• Using Polyethylene glycol (PEG) as a base, both absorption and elimination of ni­fedipine was rapid. However, when a mixture of PEG and carbopol were used as a base, a relatively high nifedipine concentration and a prolonged ac­tion were observed. These data suggest that nasal absorption can be considerably improved by choosing appropriate excipients and optimising the formulation .

Sprays vs drops-Nasal spray deposit more an­teriorly, resulting in slow clearance of sprays than of drops. The nasal bioavailability of desmopressin has been found to be significantly increased fol­lowing spray administration as compared to nasal dropS27. The clearance of nasal formulation can be influenced by viscosity of the preparation. The clearance half life (t I /2) of the nasal spray solutions

14 INDIAN 1. EXP. BIOL., JANUARY 1999

containing HPMC increased with increasing con­centration of the viscous agents 78.

Powder vs solution-Powder dosage forms of pcptides and proteins offer advantages over liquid formulation. In powder form the chemical stability of the drug is usually increased, preservatives in the formulation is not required, and it is possible to administer larger amounts of drugs and excipients. Intranasal delivery of a nafarelin79 powder dosage form with high molecular weight dextrans pro­vided a higher peptide absorption than a liquid formulation. A clinical study compairing the ad­ministration of powder and solutions of glucagon and human calcitonin with dihydrofusidate as en­hancer through nasal route indicated the powder formulations were as effective as the spray solu­tions47

. In another study, it was reported that in rabbits nasal powder dosage forms of salmon cal­citonin were twice as effective as solutions80

•

Bioadhesive as nasal delivery systems

To reduce the nasal clearance and improve the nasal drug absorption, bioadhesives were intro­duced in nasal drug delivery. These systems util­ised bioadhesive gels or microspheres. The powder dosage form of insulin mixed with several bioad­hesive excipients such as crystalline cellulose, hy­droxypropyl cellulose and neutralized carbopol 934, showed different degrees of enhanced nasal absorption of insulin in dog8 1

• The absorption of insulin from the nasal mucosa was fastest in the preparation with crystalline cellulose and was sus­tained in the preparation with neutralized carbopol 934. A system composed of insulin and CP 934 freeze dried together prior to mixing with crystal­line cellulose, resulted in the most efficient en­hancement of nasal absorption. A polyacrylic acid gel bioadhesive system improved the absorption of insulin and calcitonin in rats82

.

The microspheres form a gel-like layer which is cleared slowly from the nasal cavity, resulting in prolonged residence time of the drug formulations. An increased contact time would possibly in­creased the absorption efficiency of the drug.

Bioadhesive microspheres containing materials such as starch, albumin and dextran with particle sizes of 40-60 /lm have been found to be cleared from the nasal cavity much slower than solutions ~nd powder preparations83

. The absorption en-

hancement by starch microspheres is not only re­lated to their mucoadhesive properties, but also to their own inherent absorption -promoting effect by widening the spaces between the tight junctions. Insulin and starch micro spheres administered na­sally to rats resulting in rapid decrease in blood glucose levels. Nasal bioavailability was found to be 30% when compared to i.v. dose.

Limitations of nasal drug delivery systems (1) Nasal cavity provides smaller absorption

surface area when compared to GIT. (2) Low bioavailability of large proteins. (3) Histological toxicity of absorption en­

hancers used in nasal drug delivery is not yet clearly established.

(4) Nasal irritation leads to inconvenience. (5) Question of untoward immunogenic effects

from molecules arising with nasal delivery sys­tems.

(6) The route is adversely affected by local dis­orders such as rhinits and pathophysiological changes.

(7) Large interspecies differences in nasal drug absorption.

During pharmacokinetic and fom1Ulation studies of nasally administered drug severe limitations in the interpretation of the results may occur. Firstly, intramodel differences appear to exist (anaesthe­tised versus conscious animals). Secondly, large interspecies di fferences in the nasal absorption of certain drugs have been found. The anaesthetised rat model by Hirai et al.84 is widely employed for studying transport across the nasal mucosa. But rabbits, dogs, sheep and monkeys are also fre­quently used to investigate nasal drug absorption in vivo. It is difficult to compare studies using dif­ferent animal models due to variations in experi­mental conditions and dosage forms . Nasal peptide and protein absorption vary considerably, depend­ing on the drug and absorption enhancer used.

Conclusion The nose ils a complex organ with multiple

functions. The nasal cavity provides a highly vas­cularised surface of the nasal mucosa for the ab­sorption of drugs. The main advantages of the na­sal route of administration are that the drug degra­dation in the gastrointestinal tract is eliminated,

AGARWAL & MISHRA: INTRANASAL DRUg 'DELIVERY SYSTEM 15

hepatic first-pass metabolism is avoided and ab­sorption of drugs and onset of action can be achieved rapidly, The absorption of small drug molecules through nasal route appears satisfactory, and yields relatively good bioavailability, Nasal absorption of peptides is an attractive option but it has many drawbacks, e,g., low bioavailability, lo­cal irritation and toxicity on long term use. A bio­availability of 1-2% for an expensive recombinant peptide is not acceptable because of high cost as­sociated with the treatment. Therefore, it is neces­sary to find a biocompatible absorption promoter. The proposed promoters act by different mecha­nisms either separately or jointly. They may alter the mucus layer, inhibit proteases in the nasal mu­cosa, increase the membrane fluidity, widen the tight junctions, etc. However, a major drawback with all these enhancers is their local irritation and toxicity on the nasal mucosa. Furthermore, the immunological consequences of nasal administra­tion of peptides have also to be investigated, espe­cially the local immunization and production of IgA which can induce inflammatory reactions and prevent absorption of biologically active peptides. The efficacy of the enhancers in nasal drug ab­sorption has been shown to be greatly dependent on interspecies and experimental animal model differences, It is therefore advisable to perform human experiments at an early stage in the devel­opment of those nasal formulations which contain selective and safe absorption enhancers.

In particular, the nasal delivery of peptides and proteins is a promising alternative to injectable ro:.Jte of administration. It is very likely that in the near future more drugs will come in the market intended for systemic absorption in the form of nasal formulations,

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