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Pharmaceutical Bulletin 23
Edition: May 31, 2011
Previous Editions: August 15, 2005 / October 29, 2008
Bioadhesion
Carbopol* polymers have been used worldwide for many years to thicken, modify flow characteristics,
emulsify, and suspend insoluble ingredients. Recently, interest in their mucoadhesive properties has
grown dramatically. Today, Lubrizol Advanced Materials, Inc. polymers are the industry standard for
bioadhesive applications. Noveon* polycarbophil, Carbopol polymers, and Pemulen* polymeric
emulsifiers offer innovative opportunities in novel drug delivery systems where mucous membranes are
targeted, including ophthalmic, buccal, nasal, intestinal, vaginal and rectal applications.
Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000
The information contained herein is believed to be
reliable, but no representations, guarantees or
warranties of any kind are made as to its accuracy,
suitability for particular applications or the results to be
obtained therefrom.
The information is based on
laboratory work with small-scale equipment and does
not necessarily indicate end product performance.
Because of the variations in methods, conditions and
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Introduction to Bioadhesion
Bioadhesion (or mucoadhesion) is generally understood to define the ability of a biological or synthetic
material to stick to a mucous membrane, resulting in adhesion of the material to the tissue for a
protracted period of time. This concept has received a significant degree of attention, due to potential
applications in drug delivery and enhanced drug bioavailability which results from the lengthened period of
time in which the bioadhesive dosage form is in contact with the absorbing tissue versus a standard
dosage form.
In order for a material to be bioadhesive, it must interact with mucus, which is a highly hydrated, viscous
anionic hydrogel layer protecting the mucosa. The mucin is composed largely of flexible glycoprotein
chains, which are crosslinked as shown in Figure 1.
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Measuring Bioadhesion
Bioadhesion is a difficult phenomenon to measure. Results of bioadhesion tests vary widely depending on
the factors considered when designing the test. Some of the more common causes of differences
between measurements include the test method itself and the specific property being measured.
For instance, while most tests measure stress-strain curves at low amplitudes, test results vary in
relationship to whether the force of adhesion or the work of adhesion is measured.
The force of
adhesion, or peak adhesion strength, refers to the peak height of the stress-strain curve, which represents
the force required to separate the probe from the substrate. Work of adhesion is the area under the
stress-strain curve. It incorporates information regarding the energy required to completely sever the
adhesive bond. Some tests also incorporate tangential shear.
There are many different models typically used to describe adhesion which range from the simple to the
complex. Biological systems tend to be more complicated, which makes in vitro modeling more difficult.
Specifically, pH conditions are important to the results of the study, as greatest bioadhesion tends to be
demonstrated under acidic conditions. In addition, factors such as the ionic strength of the test fluid
especially the presence of divalent ions such as calcium will also have an impact on the measurement of
bioadhesion as test materials and models vary.
Bioadhesion Models
Here are adhesion models for biological systems listed in order of increasing complexity:
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To further complicate in vitro / in vivo correlations, the rate of mucus turnover will have an impact on in
vivo tests. Therefore, predictions of adhesion are very difficult, even in a simple system consisting of
adhesive and flat impermeable substrate.
The graphs shown later in this Bulletin demonstrate test differences seen for Carbopol polymers. In most
in vitro models, the question is whether adhesion to the substrate or cohesion of the material to itself is
actually being measured.
One method of measuring bioadhesion is by the use of a Texture Analyzer. These are versatile instruments
capable of measuring forces in compression or extension, and can be programmed with various hold times,
and output data through a computer interface. Many probes and test jigs are available from the
manufacturers, but custom ones may be easily fabricated in any machine shop. Examples of equipment
available from two manufacturers, and their capabilities, may be seen at the following websites:
http://www.texturetechnologies.com/TAXTPlus Texture Analyzer.html
http://www.textureanalysis.com/.
4. Add small amounts of Tris Amino to the dispersion while mixing at 800-1,000
rpm until the pH measures 4.5.
5. Add an additional 10g of distilled water to the mixture to bring the total weight to
500g. The resulting gel is now 1.2% polymer.
6. Measure the viscosity with a Brookfield Viscometer, which has been equipped
with a suitable spindle rotating at 20 rpm.
7. Take two samples of the gel, place in test tubes and centrifuge.
8. Place the sample on a brass mount piece, and screw the mount onto the
platform.
9. Level the sample with a spatula and ensure no air bubbles are present.
10. The Texture Analyzer is then used to measure the peak adhesion force and the
work of adhesion.
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polycarbophil and Carbopol polymers are in clinical trials worldwide for bioadhesive drug delivery
systems, while formulations utilizing Pemulen polymeric emulsifiers are under development. Figure 2
shows a comparison of Carbopol polymer versus several other bioadhesive materials.
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the solubility of the polymer, and therefore cannot be used to determine the molecular weight of an
insoluble crosslinked polymer such as Carbopol polymers or Noveon polycarbophil. We calculate
stoichiometrically and theoretically that their molecular weights could be as high as 3.5 billion due to the
interlinkage of many polymer chains.
Please see TDS-222, Molecular Weight of Carbopol and Pemulen Polymers, for more information.
Mucoadhesive Mechanism
The bioadhesive material must come into close contact with the tissue in order for bioadhesion to occur.
Polyacrylic acid polymers, such as Noveon AA-1 USP polycarbophil, Carbopol polymers and Pemulen
polymeric emulsifiers, may make excellent bioadhesives for many reasons. Due to their chemical nature,
these high-molecular-weight polymers readily swell in water, providing a large adhesive surface for
maximum contact with the mucin (the glycoprotein predominant in the mucous layer). Generally,
polyacrylic acid polymers are understood to interact with the mucin, resulting in adhesion of the polymer to
the mucin, although the exact mechanism is not yet fully understood.
Three models of real biological application systems are presented in Figure 3, arranged in order of
decreasing complexity. Model C represents the typical test performed using a mechanical tack tester and
metal plates, and does not incorporate mucus into the system. In Model B a separate phase of
intermixed Carbopol polymer and mucus between the mucus layer and the swollen Carbopol polymer
phase is formed. Studies performed on this type of system have shown that there is a marked increase in
mucus viscosity with Carbopol polymers. L.J. Kerr, et al25 describe this increase in the mucus viscosity
and microviscosity as well.
Figure 3 Models for in vivo bioadhesion
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The bioadhesive tablet (Model A) represents the most complex case of the three. In this case, there
remains a reservoir of drug entrapped in the solid polymer core of the tablet, which will diffuse slowly as
the outer layer of the tablet is hydrated. This gel layer will also interact with the mucin on the contact
surface.
Overall delivery (bioavailability) of the active may be increased solely by localization of the tablet or
Carbopol polymer gel near the biowall. These phenomena have been explained in the literature, and are
thought to be the result of hydrogen bonding, chain entanglement of the two hydrogels, and/or surface
effects. Whatever the mechanism, once adhered, the Carbopol polymer based vehicle is highly resistant
to being washed away.
Hydrogen Bonding
If hydrogen bonding is indeed a key part of the mechanism, the presence of a great number of carboxylic
groups which provide the ability to form hydrogen bonds is a critical characteristic that is found in all
Carbopol polymers. From an experimental design viewpoint, pH effects are then very important, as the
polymer may adhere better at acidic pH levels where they are in a highly protonated condition.
At low pH (5.0 or less), less than 10% of the Carbopol acid groups will be ionized, resulting in relatively
little stiffening by electrostatic charge repulsion, and relatively little swelling compared to fully neutralized
Carbopol polymer systems. In this regime, hydrogen bonding to polysaccharides or directly to proteins is
probably the major mechanism for bioadhesion. The pKa of Carbopol polymers is 6.00.5. Above that
point, the carboxylic acid groups are ionized to a great extent, thus reducing hydrogen bonding.
Under more alkaline conditions, the Carbopol gels are very highly swollen, and the chains are stiffened
by electrostatic repulsion of the anionic charges along the backbone. Specific adhesion is still possible,
however, because the polycarboxylate will interact with cationic (protonated or quaternary) bases and with
polyvalent ions. Calcium, magnesium and other polyvalent ions bound on proteins or polysaccharides will
offer such binding sites for Carbopol polymer gels.
Recent work by S.A Mortazavi42 suggests that hydrogen bonding is indeed part of the mechanism, as the
addition of the hydrogen-bond breaking agents urea and potassium thiocyanate to a homogenized mixture
of mucus and Carbopol 934P NF polymer at pH 6.2 resulted in a reduction in the storage modulus (G')
and the loss modulus (G") of the mixture. This work also suggests that chain interpenetration is key in the
mucoadhesive mechanism.
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Chain Interpenetration
Other researchers have suggested that chain
flexibility is critical. They believe that chain interpenetration, diffusion and entanglement with the
mucin accounts for bioadhesion at less than
optimum pH levels. Figure 4 shows the theoretical
interpenetration of a Carbopol polymer with the
mucin during bioadhesion.
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Carbopol polymers and Noveon polycarbophil have been used for many years in ocular applications to
provide bioadhesive effects. These benefits have been studied widely by several universities, and
privately within major companies conducting ophthalmic research.
Park and Robinson44 showed that polyacrylic acid solutions bind to cultured human conjunctival epithelial
cells as measured by a fluorescent probe technique. Ho-Wah Hui and Robinson21 tested the delivery of
14
C-labeled progesterone in a Noveon AA-1 USP polycarbophil based gel to the precorneal pockets of
rabbits. Results showed a prolonged presence of the drug, and higher tissue concentrations versus the
control. In this study, when the force of adhesion was measured using a modified precision balance, it
was found that the bioadhesion was one-fourth that found in the stomach. Hui and Robinson hypothesized that this is due to the significantly lower amount of mucin in the eye.
Davies et al9 performed a similar study with pilocarpine with several bioadhesive materials, and found that
Carbopol 934P NF polymer was more bioadhesive than polyvinyl alcohol, which was more bioadhesive
than the phosphate buffer. The same relationship was observed when the bioavailability of the drug was
measured in the rabbit model.
Lubrizol Pharmaceutical Polymers in Nasal Bioadhesive Applications
Carbopol polymers and Noveon polycarbophil have attributes that make them ideal for nasal delivery.
In addition to their bioadhesive character, these polymers are shear thinning, which means that a very
viscous gel (greater than 50,000 centipoises) can be formulated, which will then mist when sprayed in the
nose. The field of nasal bioadhesion is still under exploration, but exciting work has already been done.
Nagai et al43 showed that a freeze-dried powder using Carbopol 934P NF polymer gave enhanced insulin
bioavailability when delivered nasally. Chu et al7 demonstrated that propranolol delivered in a hydrogel
based on Carbopol 934P NF polymer had increased bioavailability compared to saline solution in animal
studies.
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Lubrizol Pharmaceutical Polymers in Buccal Bioadhesive Applications
The buccal cavity is of interest in the delivery of certain drugs which are sensitive to pH or enzyme attack,
or are highly metabolized in the liver. In these types of situations, sublingual or other buccal delivery
systems which are fixed in place are of great value. A number of studies have been performed at 3M
Pharmaceuticals.
One 3M report, written by R.A. Scherrer et al48 describes a study in which digoxin, theophylline,
nitroglycerine, estradiol and morphine were formulated into bioadhesive buccal tablets. This group found
that the strength of the tablet adhesion and the rate of drug release were proportional to the concentration
of the Noveon AA-1 USP polycarbophil, as well as to the initial hydration level of the polycarbophil. In
their tablet, the optimum polycarbophil concentration was 60% and the minimum initial hydration level 2%.
Therapeutically effective blood levels were found in caged and fed dogs. Bens et al3 tested lipophilic,
nonionized indole derivatives with molecular weights of less than 500 in a system similar to Scherrers.
They found that the tablet stayed six hours on the human gum, and that the human pharmacokinetics
correlated well with those determined in the dog model.
Jian-Hwa Guo16, also with 3M Pharmaceuticals, worked with another system like Scherrers, using
Carbopol 934P NF polymer instead of polycarbophil. In this study, Guo found that Carbopol polymer
has average peel strength superior to hydroxypropyl methylcellulose, chitosan or acacia in in vitro testing.
In addition, Guo found that increasing the patch thickness increased the patch adhesion. In another
study, Guo17 determined that the strongest peel strength was found in buccal patches with a Carbopol
polymer:polyisobutylene:polyisoprene ratio of 50:43:6.25.
R.L. McQuinn, et al37 performed studies regarding the effectiveness of such a system in humans using the
opiate buprenorphine as a model drug. McQuinn reported no safety problems, and that comfort and taste
were acceptable. Pharmacologically relevant serum concentrations were attained 1-3 hours after
application, and were sustained for 12-24 hours after dosing.
Lubrizol Pharmaceutical Polymers in Vaginal Bioadhesive Applications
There are several products on the market that address the issues of drug delivery to the vagina, where it
is important that the drug be delivered locally to its absorption site. Vaginal moisturizers, as well as
hormone replacement therapies, long-lasting spermicides, fungicides and antibiotics are all ideal
candidates for bioadhesive systems. Several patents deal with some of these formulations.
Lubrizol Pharmaceutical Polymers in Rectal Bioadhesive Applications
In rectal applications, the drug is often intended for systemic delivery, therefore it is important to target the
delivery system to the lower part of the rectum where the greatest contact with the bloodstream occurs.
Carbopol polymers have been used for many years in delivering drugs rectally. Work by E.A. Hosny and
A.A. Al-Angary20 to determine the effect of varying the concentration of Noveon AA-1 polycarbophil USP
on the bioavailability and blood levels of indomethacin from polyethylene glycol suppositories in dogs
showed that as the polycarbophil concentration rose from 0-5%, plasma levels and bioavailability
improved significantly.
Lubrizol Pharmaceutical Polymers in Gastrointestinal Bioadhesive Applications
For drugs which are absorbed in the stomach or upper intestine, gastric retention systems are very
desirable, but difficult to achieve due to the peristaltic wave that flushes many systems, and the drugs they
contain, from the stomach. A number of studies show that using bioadhesive materials, such as those
supplied by Lubrizol, may increase the GI transit time by attaching to the mucin lining of the gut.
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Gastric retention - S.H.S. Leung et al33 showed that Noveon AA-1 USP polycarbophil gels may provide a
gastric retention system by swelling in the stomach and inducing a pseudofed state, thereby reducing
peristaltic contractions. This phenomenon is dependent on viscosity: the higher the viscosity, the fewer
the contractions. For instance, H.S. Chng et al7 found that Noveon AA-1 USP polycarbophil labeled with
51
Cr was retained for 17 hours in rabbit stomach versus a control of 8 hours. Crosslinked polyacrylic acid
tagged with 14C was studied in vivo in rats by R.F. Riley et al.54 By hour 6, it had passed through the small
intestine and resided primarily in the first half of the large intestine.
Another study by M.A. Longer et al34 showed that the bioavailability of chlorothiazide delivered in a mixture
of 3:7 albumin beads to Noveon AA-1 USP polycarbophil was 1.95 times higher in the rat than the
control.
Additional in vitro work by Y. Akiyama et al1 demonstrated that polyglycerol ester of fatty acid-based
microspheres, which were coated or dispersed with Carbopol 934P NF showed prolonged lag time
through the stomach, and then transit through the small intestine with zero-order release kinetics in fasted
rats, as compared to the microspheres that contained no Carbopol 934P NF polymer.
Protein and peptide protection a significant amount of work has shown that polyacrylic acid based
materials show superior protection capability for protein and peptide drugs. Much of this work has been
done at the University of Leiden under the direction and guidance of Dr. Junginger.27,28,35,36 The focus of
this research has been on Noveon AA-1 USP polycarbophil and Carbopol 934P NF polymer. These
polymers have been shown to inhibit proteolytic degradation of proteins and peptides by mucosal
enzymes, as well as trypsin activity, probably by chelation of the calcium ion which activates the trypsin.
Intestinal absorption of peptide improved in vitro, in situ in a perfused intestinal loop and in vivo in the rat.
The action of these polymers was also shown to be limited by the rate of mucous turnover. In addition, a
study by D.A. Hutton et al22 demonstrated that Carbopol 934P NF polymer inhibits colonic mucolytic
activity of luminal proteinase.
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Figures 6 through 15 in the following pages describe data generated on Carbopol polymers, Noveon
polycarbophil and Pemulen polymeric emulsifiers using the bioadhesion tester described previously.
Keep in mind that the results are organized to show the effects of viscosity on bioadhesion
measurements, with Carbopol 910 NF having the lowest viscosity, at 2,500 cPs, and Carbopol 940 NF
having the highest, at 68,500 cPs. The figures show the results of some very simple tests using 14
different Lubrizol polyacrylic acid gels at 1.2% solids in demineralized water, neutralized to a pH of 4.5
0.1. This pH was used to demonstrate the viscosity of these products under conditions favorable for
hydrogen bonding to polysaccharide oligomers such as are found in mucin and other biological materials.
Even in this simple system, with a simple viscoelastic adhesive mass and smooth rigid substrates of
simple geometry, complex results arose.
The contact pressure and time of contact affected both the peak adhesive strength and the work of
adhesion. At low contact force and time (2 psi for 2 seconds), the peak adhesive strength generally
decreased with a corresponding increase in gel viscosity. In all cases, increasing the contact increased
the adhesive strength slightly. (See Figures 6, 7, 8 and 9).
At high contact force, this relationship seems to reverse itself: the measured peak adhesive strength was
lower for low viscosity systems (and sometimes apparently lower than for the low contact force/ short time
data) and higher for the high viscosity systems. Again, longer impingement times tended to increase the
adhesion force, if only slightly. These data suggest that the contact pressure is the more important of the
two variables when measuring Carbopol polymers with this method.
In contrast to the peak adhesive strength, the total work of adhesion increased with adhesive viscosity for
all combinations of contact force and time. (See Figures 10, 11, 12 and 13.)
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Another perspective on this simple model can be gained by considering tack (work of adhesion) versus
peak adhesive strength. This number represents an estimate of the distance over which the adhesive
forces are acting. As shown in Figure 14, tack declines as peak adhesive strength increases at low
pressure, while Figure 15 demonstrates the reversal of this trend at higher pressures.
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Akiyama, Y., Nagahara, N., Hirai, S., Toguchi, H., In Vitro and In Vivo Evaluation of Mucoadhesive Microspheres
Prepared for the Gastrointestinal Tract Using Polyglycerol Esters of Fatty Acids and a Poly(Acrylic Acid)
Derivative, Pharmaceutical Research, 12 (3), 397-405, 1995.
Anlar, S., Capan, Y. and Hincal, A. A., Physico-Chemical and Bioadhesive Properties of Polyacrylic Acid
Polymers, Pharmazie, 48(4), 285-7, 1993.
Bens, L., DeGrande, G., Horriere, F., Karsenty, H. and Lagain, D., A New Buccal Delivery System for an Indole
Derivative, Proceed. Intl. Symp Controlled Release Bioact. Mater., 19, 1992.
Bouckaert, S., Schauttet, H., Lefebvre, R.A., Remon, J.P. and Van Clooster, R., Comparison of Salivary
Miconazole Concentrations after Administration of a Buccal Bioadhesive Slow-Release Tablet and an Oral Gel,
Eur. J. Clin. Pharmacol., 43(2) 137- 40, 1992.
Bouckaert, S. and Remon, J.P., In Vitro Bioadhesion of a Buccal Miconazole Slow- Release Tablet, J.Pharm.
Pharmacol., submitted.
Bottenberg, P., Cleymaet, R., De Muynck, C, Remon, P.P., Coomans, D., Michotte, Y. and Slop, D.,
Development and Testing of Bioadhesive Fluoride Containing Tablets for Oral Use, J. Pharm. Pharmacol.,
43(7), 457-64, 1991.
Chng, H.S., Park, H., Kelly, P. and Robinson, J.R., Bioadhesive Polymers as Platforms for Oral Controlled
Release Drug Delivery. II. Synthesis and Evaluation of Some Swelling, Water-Insoluble Bioadhesive Polymers,
Journal of Pharmacological Science, 74, 229, 1985.
Chu, J.S., Chadrasekharan, R., Amidon, G., Weiner, N.D. and Goldberg, A.H., Viscometric Study of Polyacrylic
Acid Systems as Mucoadhesive Sustained-Release Gels, Pharmaceutical Res., 9(11), 1408-12, 1991.
Davies, N.M., Farr, S.J., Hadgraft, J. and Kellaway, I.W., Evaluation of Mucoadhesive Polymers in Ocular Drug
Delivery I. Viscous Solutions, Pharm. Res. 8(8), 1039-43, 1991.
10
Davies, N.M., Farr, S.J.,Hadgraft, J. and Kellaway, I.W., Evaluation of Mucoadhesive Polymers in Ocular Drug
Delivery II. Polymer-Coated Vesicles, Pharm. Res. 9(9), 1137-44, 1992.
11
Duchne, D., Touchard, F. and Peppas, N.A., Pharmaceutical and Medical Aspects of Bioadhesive Systems for
Drug Administration, Drug Development and Ind. Pharm. 14(2&3), 283-318, 1988.
12
Durrani, A.M., Davies, N.M., Thomas, M. and Kellaway, I.W., Pilocarpine Bioavailability from a Mucoadhesive
Liposomal Ophthalmic Drug Delivery System, J. Pharm. Pharmacol., 43(15), 1991.
13
Garcia-Gonzales, N., Blanco-Fuente, H., Anguiano-Igea, S., Delgado-Charro, B., Otero- Espinar, F.J. and BlancoMendez, J., In Vitro Characterization of Bioadhesive Metoclopramide Tablets for Buccal Applications Prepared
with Polyacrylic Acid (Carbopol 907, 941, 934, 940) and Hydroxypropyl Methylcellulose, S.T.P. Pharma. Sci.,
2(6), 494-9, 1992.
14
Garcia-Gonzales, N., Kellaway, I.W., Blanco Fuente, H., Anguiano Igea, S., Delgado Charro, B., Otero Espinar,
F.J. and Blanco Mendez, J., Influence of Glycerol Concentration and Carbopol Metoclopramide Hydrogels
15
Guo, J-H., Investigating the Bioadhesive Properties of Polymer Patches for Buccal Drug Delivery (Carbopol
934P), J. Controlled Rel., 28(1), 272-273, 1994.
16
Guo, J-H., Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Formulation, In Vitro
Adhesion and Release Properties, Drug Devel. Ind. Pharm., 20(18), 2809-2821, 1994.
17
Guo, J-H., Investigating the Surface Properties and Bioadhesion of Buccal Patches, J. Pharm. Pharmacol., 46,
647-650, 1994.
18
Harris, D., Sharma, H., Smith, A-M., Fell, J. and Taylor, D., The Assessment of Muco- Adhesive Agents for
Delaying Gastro-Intestinal Transit in Human Volunteers Using Gamma Scintigraphy, Proceed. Intl. Symp. Cont.
Rel. Bioact. Mat., 14, 1987.
19
Helliwell, M., Martin, G.P. and Marriott, C., Modification of Surface Carboxyl Group of Microcapsules Using a
Water-Soluble Carbodiimide, Drug Targeting Delivery, (Microencapsulation of Drugs), 65-80, 1994.
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20
Hosny, E.A. and Al-Angary, A.A., Bioavailability of Sustained-Release Indomethacin Suppositories Containing
Polycarbophil, Intl. J. Pharma., 113 (Jan 16), 209-213, 1995.
21
Hui, H-W. and Robinson, J.R., Ocular Delivery of Progesterone Using a Bioadhesive Polymer, Intl. J. Pharma.,
26 (1), 203-213, 1985.
22
Hutton, D.A., Pearson, J.P., Allen, A. and Foster, S.N.E., Mucolysis of the Colonic Mucous Barrier by Faecal
Proteinases: Inhibition by Interacting Polyacrylate, Clinical Science, 78, 265-271, 1990.
23
Ito, R., Machida, Y., Sannan, T. and Nagai, T., Magnetic Granules: A Novel System for Specific Drug Delivery to
Esophageal Mucosa in Oral Administration, Intl. J.Pharm., 61(1-2), 109-17, 1990.
24
Jacques, Y., Chulia, D., Verain, A. and Ozil, P., Study on a Mucoadhesive Tablet Intended for the Buccal Cavity,
Pharm. Acta Helv., 64(5-6), 163-7, 1989.
25
Kerr, L.J., Kellaway, I.W., Rowlands, C. and Parr, G.D., The Influence of Poly(Acrylic) Acids on the Rheology of
Protein Gels, Proceedings of the Intl. Sym. Cont. Rel. Bioact. Mat. 17, 122 , 1990.
26
Lee. V., Sasaki, H., Fabrizio, Saettone, M. and Chetoni, P., Influence of Drug Release on Systemic Timolol
Absorption From Polymeric Ocular Inserts in the Pigmented Rabbit, J. Ocul. Pharmacol., 10(2), 421-429, 1994.
27
de Leeuw, B.J., Lueen, H.L., Prard, D., Verhoef, A.C., de Boer, A.G. and Junginger, H.E., The Effect of
Mucoadhesive Poly(Acrylates) Polycarbophil and Carbomer on Zinc and Calcium Dependent Proteases,
Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22, #2123, 1995.
28
Lehr, C.M., Bouwstra, J.A., Tukker, J.J., Verhoef, A.C., de Boer, A.G., Junginger, H.E. and Breimer, D.D., Oral
Bioadhesive Drug Delivery Systems - Effects on G.I. Transit and Peptide Absorption, Pharm. Res., 7(9)
September, 1990 (Suppl.) PDD 7226, 1990.
29
Lehr, C.M., Bouwstra, J.A., Tukker, J.J. and Junginger, H.E., Intestinal Transit of Bioadhesive Microspheres in an
In Situ Loop in the Rat - A Comparative Study with Copolymers and Blends Based on Poly(Acrylic Acid), J.
Controlled Rel., 13(1), 51- 62, 1990.
30
Lehr, C.M., Bouwstra, J.A., Bodde, H.E. and Junginger, H.E., A Surface Energy Analysis of Mucoadhesion:
Contact Angle Measurements on Polycarbophil and Pig Intestinal Mucosa in Physiologically Relevant Fluids,
Pharm. Res., 9(1), 70-5, 1992.
31
Lehr, C.M., Bouwstra, J.A., Joke, A., Spies, F., Onderwater, J., Van Het Noordeinde, J., Vermeij-Keers, C., Van
Munstern, C. and Junginger, H.E., Visualization Studies of the Mucoadhesive Interface, J. Controlled Release,
18, 249-26, 1992.
32
Leung, S-H. and Robinson, J.R., Polymer Structure Features Contributing to Mucoadhesion. II., J. Contr. Rel.,
12(3), 187-94, 1990.
33
Leung, S-H., Irons, B.K. and Robinson, J.R., Polyanionic Hydrogel as a Gastric Retentive System, J. Biomater.
Sci, Polymer Edition, 4(5), 483-492, 1993.
34
Longer, M.A., Chng, H.S. and Robinson, J.R., Bioadhesive Polymers as Platforms for Oral Controlled Drug
Delivery. III. Oral Delivery of Chlorothiazide Using a Bioadhesive Polymer, J. Pharm. Sciences, 74(4), 406-411,
1985.
35
Lueen, H.L., Lehr, C.M., Rentel, C.O., Noach, A.B.J., de Boer, A.G., Verhoef, J.C., Merckle, H.P. and Junginger,
H.E., Effect of Poly(Acrylates) on the Enzymatic Degradation of Peptide Drugs by Intestinal Brush Border
Membrane Vesicles, J. Controlled Rel., 29(1), 329-338, 1993.
36
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BIOADHESION
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