muco adhesive dds

Journal of Pharmacy Research Vol.3.Issue 8.August 2010

D.A.Bhatt et al. / Journal of Pharmacy Research 2010, 3(8),1743-1747

1743-1747

Review ArticleISSN: 0974-6943 Available online through

www.jpronline.info

*Corresponding author.Devesh A Bhatt,18, Vikas Tenements,Nr. Zydus Cadilla High School,Jivraj Park,Ahmedabad- 380051,Gujarat.Tel.: 09823605535, 09510097166E. Mail: [email protected]

INTRODUCTION

Mucoadhesive Drug Delivery Systems : An OverviewD.A.Bhatt*, A. M. PetheSVKM’s, NMIMS, School of Pharmacy and Technology Management Shirpur, Dist. Dhule, M.S., India. Pin- 425405Received on: 18-04-2010; Revised on: 15-05-2010; Accepted on:17-07-2010

ABSTRACTToday, a pharmaceutical scientist is well versed with the fact that the overall action of a drug molecule is not merely dependent on its inherent therapeuticactivity, rather on the efficiency of its delivery at the site of action. Many drug delivery systems (DDS) are aimed to sustain drug blood concentration andcontrolling the rate of drug delivery to the target tissue, but mucoadhesion is one of the most prominent and latest systems in the design of gastro retentivedrug delivery systems. It prolongs the residence time of the dosage form at the site of application or absorption and facilitates an intimate contact of thedosage form with the underline absorption surface and thus contributes to improved and / or better therapeutic performance of the drug. In recent years manysuch mucoadhesive drug delivery systems have been developed for oral, buccal, nasal, gastrointestinal, rectal and vaginal routes for both systemic and localeffects.

Key words: Therapeutic activity, delivery, target tissue, mucoadhesion, contact.

Oral drug delivery has been known for decades as the most widelyutilized route of administration among all the routes that have been explored forthe systemic delivery of drugs via various pharmaceutical products of differentdosage forms. An ideal DDS should aid in the optimization of drug therapy bydelivering an appropriate amount to the intended site and at a desired rate. Byand large, a DDS may be employed for spatial placement (i.e., targeting a drugto a specific organ or tissue) or temporal delivery (i.e., controlling the rate ofdrug delivery to the target tissue). [1]

An immediate release dosage form is administered using a fixeddosing interval which causes several potential problems as like saw tooth kinet-ics characterized by large peaks and troughs in the drug concentration-timecurve (Fig. 1), frequent dosing for drugs with short biologic half-life, and aboveall the patient noncompliance.Controlled release (CR) DDS attempt to sustaindrug blood concentration at relatively constant and effective levels in the bodyby spatial placement or temporal delivery. The idea of mucoadhesion stemsfrom the need to localize drugs at a specific region of body (e.g stomach) becausemany drugs show poor bioavailability (BA) in the presence of intestinal meta-bolic enzymes like cytochrome P450 (CYP3A), abundantly present in theintestinal epithelium. [2]

Another problem associated with the performance of CR systemsis that some drugs are absorbed in a particular portion of the GIT only or areabsorbed to a different extent in various segments of the GIT. Such drugs show‘absorption window’, which signifies the region of GIT from where absorptionoccurs primarily. Drugs having site-specific absorption are difficult to design asoral CRDDS because only the drug released in the region preceding and in closevicinity to the absorption window is available for absorption. After crossing theabsorption window, the released drug goes waste with negligible or no absorp-tion (Fig. 2a). This phenomenon drastically decreases the time available for drugabsorption after its release and jeopardize the success of the delivery system.The mucoadhesive drug delivery system can improve the controlled delivery ofthe drugs which exhibit an absorption window by continuously releasing thedrug for a prolonged period before it reaches its absorption site, thus ensuringits optimal bioavailabilty. (Fig. 2b). [3]

Bioadhesion [4] is defined as the attachment of a synthetic or natu-ral macromolecule to biological surface. When the biological surface is the mu-cosal tissue it is called ‘mucoadhesive.’

Composition of mucus layer [5]:

Mucus is translucent and viscid secretion which forms a thin, con-tinuous gel blanket adherent to the mucosal epithelial surface.It has the following general composition.

Water 95%Glycoprotiens and lipids 0.5-5%Mineral salts 1%Free proteins 0.5-1%

Mucus glycoprotiens are high molecular proteins possessing attached oligosac-charide units. They are:

a). L-fucoseb). D-galactosec). N-acetyl-D-glucosamined). N-acetyl-D-galactosaminee). Sialic acid

Mucoadhesion stages [6]:

I. An intimate contact between a bioadhesive and a membraneII. Penetration of the bioadhesive into the crevice of the tissue surfaceIII. Mechanical interlocking between mucin and polymer.

Potential sites for mucosal drug delivery [7]:

From the fig. 3, there are 6 potential sites of mucosal delivery:1.Ocular2.Nasal3.Gastrointestinal4.Oral transmucosal

- Buccal- Sublingual 5. Rectal 6. Vaginal



1743-1747

Mechanisms of Mucoadhesion [8]:

1. Hydration mediated adhesion: Certain hydrophilic polymers have the ten-dency to imbibe large amount of water and become sticky, thereby acquiringbioadhesive properties.2. Bonding mediated adhesion:

For adhesion to occur, molecules must bond across the interface. These bondscan arise in the following way.

(a) Ionic bonds(b) Covalent bonds(c) Hydrogen bonds(d) Van-der-waals bonds (e) Hydrophobic bonds

Theories of bioadhesion:

a). Electronic theoryBecause of different electronic properties of the mucoadhesive polymer and themucus glycoprotein, electron transfer between these two surfaces occurs.b). Absorption theoryPrimary and secondary chemical bonds of the covalent and non-covalent typesare formed upon initial contact between the mucus and the mucoadhesivepolymer.c). Wetting theoryIt describes the ability of a bioadhesive polymer to spread on biological sur-faces.d). Diffusion theoryDiffusion of the bioadhesive polymer chain into the mucus network creates anentangled network between the two polymers.e). Fracture theoryIt relates the force required for the detachment of polymers from the mucus tothe strength of their adhesive bond.

Factors affecting mucoadhesion [9]:

A). Polymer related factors

1. Molecular weight of polymer2. Concentration of active polymer4. Spatial conformation5. Hydration (swelling)6. Charge

B). Environment related factors

1. pH:2. Applied strength3. Contact time:

4. Swelling:C). Physiological variables1. Mucin properties2. Mucin turnover3. Disease states

Classification of Mucoadhesive polymers [10]: They are classified as shownin Table 1.

Evaluation of mucoadhesive dosage forms [11-14]:

1. Bioadhesion test: By tensile strength, shear strength, Fluorescent probemethod, Atomic force microscopy (AFM), falling liquid film method, Adhesionnumber2. Permeability study: Using different diffusion cells2. Release rate study: Using USP dissolution test

1. OCULAR DRUG DELIVERY

A) Liquid dosage forms [15-18]:

1. Viscous solutions: Polymers used are Cellulose derivatives, Acrylates,Hyaluronan, Chitosan, Polysaccharides, and Thiomers.2. Particulate systems: Liposomes, Microspheres and nanospheresPolymers used are Acrylates, Poly (epsilon-caprolacton), Poly (D,L-lacticacid) and poly(D,L-lactide-co-glycolide).

B) Semi-solid dosage forms [19-21]:

1.HydrogelsTypes of hydrogel are:Preformed gels: - cellulose, PVA, Hyaluronic acid, CarbomerInsitu forming gels:- gellan gum, Poloxamer (Pluronic F-127)2. Pseudolatex: CAP- cellulose acetate phthalate.3. Ionically induced gelation: Gellan gum is an anionic exocellular polysaccha-ride.

C) Solid dosage forms [22, 23]:

1. Inserts:a) Soluble inserts: Polymers such as Collagen, PVA, cellulose based polymers.Commercial product: - Lacristat Commercial product: - Bio-cor, medilenb) Insoluble inserts: Polymers used are Hyaluronan, Chitosan, Polysaccha-rides. Commercial product:-Ocusertc) Bioerodible inserts: Polymers used are Cellulose derivatives, Acrylates, Poly(ethylene oxide) band Thiomers.

Fig. 1: Plasma level profiles showing conventional and controlled release dosing.

Fig. 2: (a) Conventional dosage forms (b) Mucoadhesive drug delivery system



1743-1747

2. NASAL MUCOADHESIVE DRUG DELIVERY

A) Small organic molecules [24]:

-Gentamycin using HPMC-Vancomicin and Tobramycin using chitosan.

B) Macromolecules:

-Vaccines and DNA Eg, PEG-coated polylactic nanospheres, chitosan-coatedpolylacic-glycolic acid nanospheres and chitosan nanospheres [25].-Protiens Eg, cyanocobalamin is incorporated into microcrystalline cellulose,dextran microspheres (26) and crospovidone.Also Carbopol gels and chitosan microparticles can be used for protein deliv-ery.Insulin’s nasal absorption was better with chitosan powder than chitosannanoparticles and chitosan solution formulations.

C) New generation polymers [27-30]:

- Bioadhesive graft copolymers of polymethacrylic acid and polyethyleneglygol as a powder delivery for Budesonide.- Chitosan-4-thio-butyl-amidine chitosan thioglycolic acid and cysteamineconjugates of carboxymethylcellulose and polycarbophil are some of thesenew generation polymers that are pH sensitive.- Delivery of plasmid DNA using the thermoresponsive polymer, poloxamer incombination with bioadhesive polymers polycarbophil or polyethylene oxide.

3. GASTRO RETENTIVE MUCOADHESIVE DRUG DELIVERY SYS-TEM

Criteria [31-33]:

•Drugs those are primarily absorbed in the stomach;•Drugs those are poorly soluble at an alkaline pH;•Drugs with a narrow window of absorption;•Drugs absorbed rapidly from the GI tract; and•Drugs those degrade in the colon.•Drugs acting locally in the stomach;

A). Mucoadhesive dosage forms [34-37]:

•Mucoadhesive microspheres and nanoparticles (amoxicillin),

•Mucoadhesive granules (furosemide),•Mucoadhesive discs (celecoxib),•Mucoadhesive tablets (atenolol, metformin, nifedipine, felodipine, glipizide,ciprofloxacin, sotelol, acyclovir, gabapentin, ofloxacin, erythropoietin,rosiglitazone, itraconazole, diltiazem, indomethacin

B). Mucoadheive Polymers [38-41]:

Sodium CMC, HPMC, polyacrylate polymers, Carbopol®, Spheromer® III,sodium alginate, guar gum, polyethylene oxide

4. ORAL TRANS-MUCOSAL DRUG DELIVERY

It is subdivided into [42, 43]:I. Sublingual drug delivery: Via the mucosa of the ventral surface of the tongueand floor of the mouth under the tongue;II. Buccal drug delivery: Via the buccal mucosa – the epithelial lining of thecheek, the gums and also the upper and lower lips.

Transport route and mechanisms [44-46]:

- Paracellular route: Between adjacent epithelial cells- Transcellular route: Across the epithelial cell

Physiological factors affecting oral transmucosal bioavailability are [47]:

Inherent permeability of epithelium, thickness of the epithelium, blood supply.

Formulation design [48-50]:

1. Bioadhesive agents:2.Penetration enhancers: 3-lauryl ether, Aprotinin, Azone, Benzalkonium chlo-ride, Cetylpyridinium chloride, Cetyltrimethylammonium bromide,Cyclodextrin,Cod – liver oil extract, Dextran sulfate, Lauric acid, Lauric acid,Propylene glycol, SodiumEDTA, Sodium glycocholate, Sodiumglycodeoxycholate3. Enzyme Inhibitors: aprotinin, bestatin, puromycin and some bile salts.4. Solubility Modifiers: cyclodextrin

Formulations [51-52]:

A). Buccal delivery:1. Buccal Tablets:2. Buccal patch:3. Buccal film:4. Buccal gel and ointment:

Fig. 3: Potential sites for mucosal drug delivery

TABLE 1: CLASSIFICATION OF MUCOADHESIVE POLYMERS:

Source Examples

Semi-natural/natural Agarose, chitosan, gelatin, Hyaluronic acid, Various gums (guar,hakea, xanthan, gellan, carragenan, pectin, and sodium alginate),starch, sulfated polysaccharides.

Synthetic Cellulose Carboxy methyl cellulose(CMC), sodium CMC, Hydroxy ethylederivatives cellulose (HEC), Hydroxy propyly cellulose (HPC), Hydroxy

propylymethyl cellulose (HPMC), Methyl cellulose (MC),methylhydroxyethylcellulose

Synthetic Poly(acrylic Carbopol, Polycarbophil, polyacrylates, poly(methylvinylether-acid) based polymers co-methacrylic acid), poly(2-hydroxyethyl methacrylate), poly

(acrylic acid-co ethylhexylacrylate), poly(methacrylate),poly(alkylcyanoacrylate), poly(isohexylcyanoacrylate),poly(isobutylcyanoacrylate), copolymer of acrylic acid and Polyethylene glycol

Others Poly(N-2-hydroxypropyl methacrylamide) (PHPMAm),polyoxyethylene, Poly vinyl alcohol, Polyvinyl pyrollidone,thiolated polymers, Poloxamers



1743-1747

CONCLUSION

The focus of pharmaceutical research is being steadily shifted fromthe development of new chemical entities to the development of novel drugdelivery system (NDDS) of existing drug molecule to maximize their effectivein terms of therapeutic action and patent protection. In the recent years theinterest is growing to develop a drug delivery system with the use of amucoadhesive polymer that will attach to related tissue or to the surface coatingof the tissue for the targeting various absorptive mucosa such as ocular, nasal,buccal, vaginal etc. Many drug delivery and pharmaceutical companies areexploiting this technology to reexamine active ingredients that were abandonedfrom formulation programs because of their poor stability in intestine, etc.Therefore a primary objective of using mucoadhesive systems would be achievedby obtaining a substantial increase in residence time of the drug for local drugeffect and to permit once daily dosing. There is no doubt that mucoadhesion hasmoved into a new area with these new specific targeting compounds withresearchers and drug companies looking further into potential involvementof more smaller complex molecules, proteins and peptides, and DNA for futuretechnological advancement in the ever-evolving drug delivery arena Themucoadhesive system will continue to appeal to both pharmaceutical research-ers and the pharmaceutical industry.

REFERENCES

1. Smart J D. The basics and underlaying mechanisms of mucoadhesion. Adv Drug Del Rev2005; 57: 1556-1568.

2. Lim ST, Martin GP, Berry DJ, Brown MB. Preparation and evaluation of the in vitro drugrelease properties and mucoadhesion of novel microspheres of hyaluronic acid and chitosan.J Control Release 2000; 66: 281–292.

3. Chowdary KP, Kamalakara GR, Bhaskar P. Mucoadhesive polymers- Promising excipientsfor controlled release. Int J Pharm Excip 2001; 3: 33-38.

4. Bernkop A, Hornof M, Zoidl T. Thiolated polymers—thiomers: synthesis and in vitroevaluation of chitosan- 2-iminothiolane conjugates. Int J Pharm 2003; 260: 229– 237.

5. Lehr CM. Lectin-mediated drug delivery: the second generation of bioadhesives. J ControlRelease 2000; 65: 19– 29.

6. Lele BS, Hoffman AS. Mucoadhesive Drug Carriers Based on Complexes of poly (acrylicacid) and PEGylated Drugs having Hydrolysable PEG-anhydride-drug Linkages. J Con-trol Release 2000; 69: 237-248.

7. Rao K V, Buri P. Novel in situ method to test polymers and coated microparticles forbioadhesion. Int J Pharm 1989;52: 265-270.

8. Hassan EE, Gallo JM. Simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharm Res 1990; 7: 491-498.

9. Park KA new approach to study mucoadhesion: colloidal gold staining. Int J Pharm1989;53:209-217.

10. Longer MA, Ch’ng H, Robinson JR. Bioadhesive polymers as platforms for oral controlleddrug delivery J Pharm Sci 1985; 74: 406-411.

11. Bala RC, Vani G, Madhusudan RY. In Vitro and In Vivo Adhesion Testing of MucoadhesiveDrug Delivery Systems. Drug Dev Ind Pharm 1999; 25: 685-690.

12. Bottenberg P,Cleymaet R,De muynck C,Remon JP,Coomans D,Michotte Y, SlopD.Development and testing of bioadhesive, fluoride-containing slow release tabletsfor oral use .J Pharm Pharmacol 1990; 43:457-464.

13. Sam AP,Van JT, Tukker J. Mucoadhesion of both film-forming and non- film forming poly-meric materials as evaluated with the Wilhelmy plate method. Int J Pharm 1989; 53: 97-105.

14. Smart JD. An in vitro assessment of some mucosa-adhesive dosage forms. Int J Pharm 1991;73: 69-74

15. Annick L. The use of mucoadhesive polymers in ocular drug delivery. Adv Drug Deliv Rev2005; 57: 1595– 1639.

16. Greaves JL, Wilson CG. Treatment of diseases of the eye with mucoadhesive delivery sys-tems. Adv Drug Deliv Rev 1993; 11: 349– 383. .

17. Law SL, Huang KJ, Chiang CH. Acyclovir-containing liposomes for potential oculardelivery. J Control Release 2000; 63: 135–140.

18. Lin HH, Ko SM, Hsu LR, Tsai YH. The preparation of norfloxacin-loaded liposomes andtheir in-vitro evaluation in pig’s eye. J Pharm Pharmacol 1996; 48: 801– 805.

19. Meisner D, Mezei M. Liposome ocular systems. Adv Drug Deliv Rev 1995; 16: 75– 93.20. Kaur IP, Smitha R. Penetration enhancers and ocular bioadhesives: two new avenues for

ophthalmic drug delivery. Drug Dev Ind Pharm 2002; 28: 353– 369.21. Alonso MJ, Sanchez A. The potential of chitosan in ocular drug delivery. J Pharm Pharmacol

2003; 55:1451– 1463.22. Davies NM, Farr SJ, Hadgraft J, Kellaway IW. Evaluation of mucoadhesive polymers in

ocular drug delivery. Pharm Res 1992; 9: 1137–1144.23. Ludwig A. The use of mucoadhesive drug delivery in ocular drug delivery . Adv Drug Del

Rev 2005; 57: 15 95-1639.24. Ishikawa F, Murano M, Hiraishi M, Yamaguchi T, Tamai I, Tsuji A. Insoluble powder formu-

lation as an effective nasal drug delivery system. Pharm Res 2002; 19: 1097– 1104.25. Callens C, Remon JP. Evaluation of starch–maltodextrin–Carbopol974 P mixtures for the

nasal delivery of insulin in rabbits. J Control Release 2002; 66: 215– 220.26. Dyer AM, Hinchcliffe M, Watts P, Castile J, Nankervis R, Smith A. Nasal delivery of insulin

using novel chitosan based formulations: a comparative study in two animal models be-tween simple chitosan formulations and chitosan nanoparticles.Pharm Res 2002; 19: 998–1008.

27. Nakamura K, Maitani Y, Lowman AM, Takayama K, Peppas NA, Nagai T. Uptake andrelease of budesonide from mucoadhesive, pH sensitive copolymers and their applicationto nasal delivery. J Control Release 1999; 61: 329– 335.

28. Park JS, Oh YK, Yoon H, Kim JM, Kim CK. In situ gelling and mucoadhesive polymer

New and emerging technologies [53, 54]:1. Sublingual delivery.Freeze-dried fast-dissolving forms2. Buccal delivery.a) Innovative drug delivery systems, such as buccal spray and phospholipidvesicles have been recently proposed to deliver peptides via the buccal route.b) A novel liquid aerosol formulation - Oralin, Generex Biotechnologyc) Phospholipid deformable vesicles, Transfersomes, have been recently de-vised for the delivery of insulin in the buccal cavity.d) Delivery of melatonin and low molecular weight heparin (LMW) –Cydotdelivery system – a patche) Delivery of gucagon-like insulinotropic peptide (GLP-1) – The Thera Techdelivery system – bilayers tablet.f) Lectins have been studied as specific bioadhesives for drug delivery in the oralcavity.

5. RECTAL MUCOSAL DRUG DELIVERY

Structure of vaginal mucosa[55,56] : The layers of the colorectal wall, proceed-ing inward from the exterior, are Perirectal adipose(fatty) tissue supported bypelvic fascia, Muscular propria, Submucosa,Mucosa.The rectum is a reservoir8-13 cm in length that ends with the voluntary muscles of the sphincter. Rectalabsorption involves release of drug in the rectum, diffusion to the rectal mucosa,absorption by tissues and transport into general circulation

Factors affecting rectal absorption [57]: Formulation (time to liquefaction ofsuppositories), volume of liquid, concentration of drug, length of rectal catheter(site of drug delivery), presence of stool in the rectal vault.

Rectal formulations [58, 59]:- Suppositories include Mucoadhesive suppositories, Mucoadhesive liquidsuppositories , and thermo reversible suppositories. Here biodhesive polymersused are sodium alginate, poloxamer. E.g Propanolol, Insulin- Bioadhesive gel- Here biodhesive polymers used are Pluronic F-127.E.g Insulin- Hydrogel- Here biodhesive polymers used are Carbophil, Sodium alginate.E.g Propranolol

6. VAGINAL MUCOSAL DRUG DELIVERY

Structure of vaginal mucosa [60-63]: It consists of the epithelium layer, laminapropria, Tunica propria, Muscularis mucosa, tunica adventitia

Factors affecting vaginal drug delivery [64] :

- Physiological factors:Cyclical changes in vaginal epithelium, Vaguinal fluid, vaginal pH, Enzymeactivity- Formulation factors: Drug release, Contact time, Concentration

Current technologies in vaginal drug delivery [65-67]:

1. Vaginal delivery of estrogen and progesterones.2. Vaginal delivery of prostaglandins3. Therapeutic peptide deliverya) GnRH analogsb) Insulin4. Antiviral vaginal deliverya) antiviral vaginal gelb) antiviral liposomal preparationc) antiviral vaginal devices5. Vaginal mucosal vaccine.6. Microparticulate system.a) Biodegradablr Starch microsphereb) Hyaluronan ester microsphere



1743-1747

Source of support: Nil, Conflict of interest: None Declared

vehicles for controlled intranasal delivery of plasmid DNA. J Biomed Mater Res 2002; 59:144– 151.

29. Ugwoke MI, E. Sam, Verbeke N, Kinget R. Bioavailability of apomorphine following intra-nasal administration of mucoadhesive drug delivery systems in rabbits. Eur J Pharm Sci1999; 9: 213– 219.

30. Ugwoke M, Agu R, Verbeke N, Kinget R. Nasal mucoadhesive drug delivery: Background,applications, trends and future perspective; Adv Drug Del Rev 2005; 57: 1640-1665.

31. Botagataj M, Mrhar A, Korosec L. Influence of Physicochemical and Biological Parameterson Drug Release from Microspheres Adhered on Vesicularand Intesitnal Mucosa. Int JPharm 1999; 177: 211-20.

32. Allen A., Pain R.H., Robson T.R., Model for the structure of the gastric mucous gel. Nature1976; 264: 88-89.

33. Dressman JB, Berardi RR, Dermentzoglou LC, Russel TL, Schmaltz SP, Barnett JL. Uppergastrointestinal pH in young healthmen and women. Pharm Res 1990; 7: 756-761.

34. Ungell AL. In vitro absorption studies and their relevance to absorption from the GI tract.Drug Dev Ind Pharm 1997; 23: 879-892.

35. Pimienta C, Lenaerts V, Cadieux C, Raymond P, Junasz J, Simard MA, Jolicoeur C.Mucoadhesion of hydroxypropyl methacrylate nanoparticles to rat intestinal ileal seg-ments in vitro. Pharm Sci 1990; 7: 49-53.

36. Harris D, Fell JT, Taylor DC, Lynch J, Sharma HT. GI transit of potential bioadhesive systemin rat. J Control Release 1990; 12: 55 -65.

37. Li SP, Pendharkar CM, Mehta GN, Karth MG, Feld KM. Sucralfate as a bioadhesive gastricintestinal retention system: Preliminary evaluation. Drug Dev Ind Pharm 1993; 19: 2519-2537.

38. Smart JD, Kellaway IW. Pharmaceutical factors influencing the rate of gastrointestinal tran-sit in an animal model. Int J Pharm 1989; 53: 79-86.

39. Mortazavi SA, Carpenter BG, Smart JD. Comparative study on the role played by mucousglycoproteins in the rheological behaviour of the mucoadhesive/mucosal interface.Int J Pharm 1993; 94: 195-201.

40. Abrahamasson B, Alpsten M, Jonsson VE, Lundberg PJ, Sandberg A, Sundgren TM,Svenheden A, Tolli J. Gastrointestinal transit of a multiple unit formulation (MetoprololCR/ZOK) and a non-disintegrating tablet with the emphasis on the colon. Int J Pharm1996; 140: 229-235.

41. Deshpande AA, Rhodes CT, Shah NH, Mallik AW. Controlled releses drug delivery sys-tems for prolonged gastric residence: An overview. Drug Dev Ind Pharm 1996; 22: 531-539.

42. Salamat MN, Chittchang M, Johnston T. The use of mucoadhesive polymers in buccal drugdelivery Adv Drug Del Rev 2005; 57: 1666-1691.

43. Bodde HE, Junginger HE. Mucoadhesive Polymers for the Buccal Delivery of Peptides,Structure-Adhesiveness Relationships. J Control Rel 1990; 13:225-231.

44. Squier CA. The Permeability of Oral Mucosa. Crit Rev Oral Biol Med 1991; 2:13-32.45. Harris D, Robinson JR. Drug Delivery via the Mucous Membranes of the Oral Cavity. J

Pharm Sci 1992; 81:1-10.46. Gandhi RB, Robinson JR. Oral cavity as a Site for Bioadhesive Drug Delivery. Adv Drug

Del Rev 1994; 13: 43-74.47. Semalty A, Bhojwani MB, Gupta GD, Shrivastav AK. Design and Evaluation of

Mucoadhesive Buccal Films of Diltiazem Hydrochloride. Indian J Pharm Sci 2005; 67:548-52.

48. Lehr C, Bouwstra JA, Kok W, Noach AB, Junginger HE. Bioadhesion by means of specificbinding of tomato lectin. Pharma Res 1992; 9: 547-53.

49. Shojaei AM. Mechanism of Buccal Mucoadhesion of Novel Copolymers of Acrylic Acidand Polyethylene Glycol Monomethylether Monomethacrylate. J Control Release 1997;47: 151-61.

50. Nagai T, Kinishi R. Buccal/gingival Drug Delivery Systems. J Control Release 1987; 6:353.

51. Langoth N, Kalbe J, Bernkop SA. Development of Buccal Drug Delivery Systems Based ona Thiolated Polymer. Int J Pharm 2003; 252: 141-48.

52. Chein H, Langer R. Oral Particulate Delivery: Status and Future Trends. Adv Drug DelivRev 1998; 34: 339-50.

53. Alur HH, Pather SI., Mitra AK, Johnston TP. Transmucosal Sustained–Delivery ofChlorpheniramine Maleate in Rabbits using a Novel, Natural Mucoadhesive gum as anExcipient in Buccal Tablets. Int J Pharm 1999; 88: 1-10.

54. Petelin M, Pavlica Z, Bizimoska S, Sentjure M. In vivo study of different ointments for drugdelivery in to oral mucosa EPR oximetry. Int J Pharm 2004; 270:83-91

55. Seham SAE, Nahed DM, Gehanne ASA, Noha MZ, Ragia AT.Development of in situ gellingand mucoadhesive Mebeverine Hydrochloride solution for rectal administration. SaudiPharm J 2003; 11: 159-177.

56. Nishihata T, Rytting JH, Kamada A, Higuchi T, Routh M,Caldwell L. Enhancement of rectalabsorption of insulin using salicylates in dogs. J Pharm Pharmacol 1983; 35: 148–151.

57. De Boer AG, Breimer DD, Pronk JJ. Rectal bioavailability of lidocaine in rats. Absence ofsignificant first-pass elimination. J Pharm Sci 1980; 69: 804–807.

58. Ichikawa K, Ohata I, Mitomi M, Kawamura S, Maeno H, Kawata H. Rectal absorptionof insulin suppositories in rabbits. J Pharm Pharmacol 1980; 32: 314–318.

59. Yoshioka S, Caldwell L, Higuchi T. Enhanced rectal bioavailability of polypeptides usingsodium 5-methoxysalicylate as an absorption promoter. J Pharm Sci 1982; 71: 593–594.

60. Valenta C. The use of mucoadhesive polymers in vaginal delivery. Adv Drug Del Rev 2005;57: 1692-1712.

61. Desphande A, Rhodes CT, Danish M. Intravaginal drug delivery. Drug Dev Ind Pharm1992; 18: 1225–1279.

62. Furuhjelm M, Karlgren Cand, Carlstrom K. Intravaginal administration of conjugated es-trogens in postmenopausal women. Int J Gynecol Obstet 1980; 17: 335–339

63. Genc L, Oguzlar C, Güler E. Studies on vaginal bioadhesive tablets of acyclovir, Pharmazie2000; 55: 297–299.

64. Elson C, Milne A, Curran D, Kydonieus A. N,O-Carboxymethylchitosan as a mucoadhesivefor vaginal delivery of levonorgestrel, Proc. Int Symp Control Release Bioact Mater 2000;27: 7201–7202.

65. Valenta C, Kast C, Harich I. Development and in vitro evaluation of a mucoadhesive vaginaldelivery system for progesterone, J Control Release 2001; 77: 323–332.

66. Benzinger DP, Edelson J. Absorption from the vagina. Drug Metab Rev 1983; 14: 137–168.

67. Robinson JR, Bologna WJ. Vaginal and reproductive system treatments using a bioadhesivepolymer, J Control Release 1994; 28: 87–94.

muco adhesive dds

Documents