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Polymer Gels as Pharmaceutical Dosage Forms: Rheological Performance and Physicochemical Interactions at the Gel-Mucus Interface for Formulations Intended for Mucosal Drug Delivery
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug delivery to the nasal and ocular mucosa faces several obstacles. One of these is from the effective clearance mechanisms present in the nose and eye. Polymer gels with suitable rheological properties can facilitate the absorption of poorly absorbed drugs by increasing the contact time of the drug with the mucosa. This has been attributed to the rheological and mucoadhesive properties of the gel. The main objective of this thesis was to investigate the importance of these features for the anticipated in vivo contact time, here exemplified by the ocular and nasal routes of administration.

The in situ gelling polymer gellan gum was found to have a favourable rheological and in vivo performance. When administered in the nasal cavity of rats, a gel was formed that could remain at the site of administration for up to 4 hours. In addition, the epithelial uptake and transfer of a 3 kDa fluorescein dextran was higher than for a mannitol solution. Therefore, it was concluded that a gellan gum formulation should be a promising strategy for nasal drug delivery.

The potential mucoadhesive properties of a variety of polymer gels were investigated using a rheological method and by measuring the tensile force required to detach the gel from a mucosa. With both methods the rheological properties of the gel were a determining factor for the results obtained. The rheological method was found to have several limitations. One of these was that a positive response, interpreted as mucoadhesion, was only seen with weak gels. The tensile method could, in contrast, detect strengthening of the mucus only for strong gels. However, this method reflects the in vivo performance of the gel better than the rheological method.

Finally, dielectric spectroscopy was explored as a tool for investigating the likelihood of intimate surface contact between the gel and the mucus layer. This novel approach involved determining the ease with which a charged particle can pass the gel-mucus interface layer, and may enable the study of the events at the interface closer to the molecular level, than is possible with the rheological and tensile strength methods.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 76
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 293
Keyword [en]
Pharmaceutics, gel, rheology, mucoadhesion, mucosal drug delivery, in situ gel, gellan gum, Carbopol, tensile strength, nasal mucosa, intranasal administration, dielectric spectroscopy
Keyword [sv]
Galenisk farmaci
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-3538ISBN: 91-554-5705-3 (print)OAI: oai:DiVA.org:uu-3538DiVA, id: diva2:163176
Public defence
2003-09-26, B21, Uppsala Biomedicinska Centrum, Uppsala, 10:15
Opponent
Supervisors
Available from: 2003-09-02 Created: 2003-09-02 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions
Open this publication in new window or tab >>Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions
1999 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 9, no 1, p. 99-105Article in journal (Refereed) Published
Abstract [en]

Gels have been successfully used to increase the mucosal contact time and hence the bioavailability of nasal and ophthalmic formulations. The use of in situ gelling polymers requires a rapid sol-gel transition that produces a strong gel for an optimal contact time. In this study, the rheological behaviour of deacetylated gellan gum (Gelrite) was analysed in order to better understand the reasons for the good performance in humans. Thermal scans were used to study gel formation and other changes in the structure of the samples when the macromolecular and ionic contents were altered. The effect the different ions in tear fluid (Na+, K+, Ca2+) had on the gel strength and the consequences of dilution due to the ocular protective mechanisms were examined. Na+ was found to be the most important gel-promoting ion in vivo. It was also found that gels are formed in tear fluid even when the concentration of Gelrite) is only 0.1%. Samples with concentrations of Gelrite of 0.5-1% do not require more ions than 10-25% of those in tear fluid to form gels. These two findings can partly explain the good performance of Gelrite in vivo. Gels with a high elastic modulus can thus be formed even though dilution of instilled drops takes place.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90715 (URN)10.1016/S0928-0987(99)00051-2 (DOI)10494003 (PubMedID)
Available from: 2003-09-02 Created: 2003-09-02 Last updated: 2017-12-14Bibliographically approved
2. Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method
Open this publication in new window or tab >>Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method
2000 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 9, no 3, p. 301-309Article in journal (Refereed) Published
Abstract [en]

A rheological method to measure mucoadhesion was evaluated for two ion-sensitive polymers, Carbopol 934 and Gelrite((R)) (deacetylated gellan gum), in a simulated physiological environment using two commercially available mucins. The method simulates the interpenetration layer in the mucoadhesion process. The elastic modulus for a polymer/mucin mixture is compared with the elastic modulus for the polymer alone, and an increase in the elastic modulus for the mixture compared to the polymer is interpreted as a positive interaction caused by mucoadhesion. In this study the influence of polymer concentration, type of mucin and experimental rheological factors, such as gap width, were examined. The choice of polymer concentration was crucial, especially with the porcine gastric mucin. We found that one is more likely to obtain positive interactions with weak gels. It was also shown that the choice of mucin has a large influence on the results obtained. Carbopol 934 interacted more strongly with the bovine submaxillary gland mucin than with the porcine gastric mucin, whereas the gel structure of Gelrite((R)) was destroyed when mixed with the bovine mucin. Furthermore, it was concluded that with hydrogels consisting of gel particles (such as Carbopol 934), rheological measurements can give highly varying results, depending on, for example, the concentration and ion-sensitivity of the polymer, the quantity of ions present, as well as the gap width of the measuring system.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90716 (URN)10.1016/S0928-0987(99)00070-6 (DOI)10594388 (PubMedID)
Available from: 2003-09-02 Created: 2003-09-02 Last updated: 2017-12-14Bibliographically approved
3. Limitations of the rheological mucoadhesion method: The effect of the choice of conditions and the rheological synergism parameter
Open this publication in new window or tab >>Limitations of the rheological mucoadhesion method: The effect of the choice of conditions and the rheological synergism parameter
2003 In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, Vol. 18, p. 349-357Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90717 (URN)
Available from: 2003-09-02 Created: 2003-09-02Bibliographically approved
4. Interpretation of mucoadhesive properties of polymer gel preparations using a tensile strength method
Open this publication in new window or tab >>Interpretation of mucoadhesive properties of polymer gel preparations using a tensile strength method
2001 In: Journal of Pharmacy and Pharmacology, ISSN 0022-3573, Vol. 53, p. 1589-1599Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90718 (URN)
Available from: 2003-09-02 Created: 2003-09-02Bibliographically approved
5. The importance of gel properties for mucoadhesion measurements: A multivariate data analysis approach
Open this publication in new window or tab >>The importance of gel properties for mucoadhesion measurements: A multivariate data analysis approach
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90719 (URN)
Available from: 2003-09-02 Created: 2003-09-02Bibliographically approved
6. Low-frequency dielectric spectroscopy as a tool for studying the compatibility between pharmaceutical gels and mucous tissue
Open this publication in new window or tab >>Low-frequency dielectric spectroscopy as a tool for studying the compatibility between pharmaceutical gels and mucous tissue
2003 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 92, no 9, p. 1869-1881Article in journal (Refereed) Published
Abstract [en]

This interdisciplinary work demonstrates how low-frequency dielectric spectroscopy, a technique that is frequently used within physics, can be used to assess the possibilities of intimate surface contact between a polymer gel and mucous tissue, which is generally considered to be the first step in the mucoadhesion process. The dielectric responses of five different gels, of freshly excised porcine nasal mucosa and of systems made by combining the two were measured. All spectra were modeled by a Randles electric circuit containing a diffusion element, a barrier resistance in parallel with a capacitance, and a high-frequency resistance. The results were used to create a measure of the compatibility between the gel and the mucus, which we have named the compatibility factor. Thus, the compatibility factor provides us with a measure of the ease with which a charged species passes the interface between a gel and the mucus layer. The compatibility factor is calculated from the high frequency (kHz region) response of the gel, of the mucosa, and of the combined system. The two highest compatibility factors in this study were obtained for gels based on crosslinked poly(acrylic acid) and chitosan, which was in agreement with the results from mucoadhesion measurements that were performed using a tensile strength method.

National Category
Engineering and Technology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90720 (URN)10.1002/jps.10451 (DOI)12950005 (PubMedID)
Available from: 2003-09-02 Created: 2003-09-02 Last updated: 2017-12-14Bibliographically approved
7. Gellan gum increases the uptake and transfer of fluorescein dextran in rat nasal epithelium
Open this publication in new window or tab >>Gellan gum increases the uptake and transfer of fluorescein dextran in rat nasal epithelium
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90721 (URN)
Available from: 2003-09-02 Created: 2003-09-02Bibliographically approved

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