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Controlled Release Gel Formulations for Mucosal Drug Delivery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug delivery to nasal or ocular mucosa for either local or systemic action faces many obstacles – these routes are protected by effective mechanisms. Gel formulations with suitable rheological and mucoadhesive properties increase the contact time at the site of absorption. However, drug release from the gel must be sustained if benefits are to be gained from the prolonged contact time.

The work presented here is the characterization of gels and the determination of the mucoadhesive properties of polymers using rheology. Gelrite gels were formed in simulated tear fluid at concentrations of polymer as low as 0.1%, and it was shown that sodium was the most important gel-promoting ion in vivo. Rheology, although it may be a questionable technique for evaluating mucoadhesive properties of polymers, showed that interactions between mucin and polymers were most likely to be seen with weak gels.

It was possible to control the release of uncharged drug substances by including surfactants that form micelles in the gel. This release depended on lipophilic interactions between the drug and the polymer and/or the micelles. Controlled-release formulations of charged drugs could be designed by mixing the drugs with oppositely charged surfactants in certain ratios. In this way, vesicles in which the drug and surfactant constituted the bilayer formed spontaneously. The vesicle formation was affected by the presence of polymer, and very small vesicles that gave a slow release rate were formed when a lipophilically modified polymer was used.

The gels were also evaluated in the Ussing chamber using porcine nasal mucosa. The rate of transport of drugs through the mucosa could be controlled by the rate of release from the formulation. Furthermore, the Ussing chamber could be used to evaluate the potential toxicity of formulations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , p. 52
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 259
Keywords [en]
Pharmacy
Keywords [sv]
FARMACI
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-1493ISBN: 91-554-5173-X (print)OAI: oai:DiVA.org:uu-1493DiVA, id: diva2:161065
Public defence
2001-12-07, B42, BMC, Uppsala, 09:15
Opponent
Available from: 2001-11-15 Created: 2001-11-15 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. Controlled drug release from gels using surfactant aggregates: I. Effect of lipophilic interactions for a series of uncharged substances
Open this publication in new window or tab >>Controlled drug release from gels using surfactant aggregates: I. Effect of lipophilic interactions for a series of uncharged substances
2001 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 90, no 9, p. 1216-1225Article in journal (Refereed) Published
Abstract [en]

Gels are often used for the delivery of drugs because they have rheological properties that will give a long residence time. Most pharmaceutical gels consist of approximately 99% water and a polymer matrix that will not hinder the release of drugs with a small molecular weight. To fully take advantage of the residence time, it is necessary to have a sustained drug release. In this paper it is suggested that surfactant micelles can be used to control the release from gels. The in vitro release under physiological conditions of five parabens from four different poly(acrylic acid) gels (Carbopol 934, 940, 1342) and one gellan gum (Gelrite) gel was measured using a USP dissolution bath modified for gels, and the diffusion coefficients were calculated. The diffusion coefficient of uncharged parabens was generally lower in gels with lipophilic modifications, such as C1342, and the greatest effect was seen for butylparaben, with a diffusion that was 25% lower than that in C934 (lacking lipophilic modification). Addition of surfactant micelles to gels delayed the release of all the uncharged drugs in all types of gels studied. The slowest release was seen for butylparaben in a lipophilically modified gel with micelles present. The diffusion coefficient in such a system was almost 30 times smaller than that in C934 without micelles.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89520 (URN)10.1002/jps.1075 (DOI)11745775 (PubMedID)
Available from: 2001-11-15 Created: 2001-11-15 Last updated: 2017-12-14
4. Controlled drug release from gels using surfactant aggregates: II. Vesicles formed from mixtures of amphiphilic drugs and oppositely charged surfactants
Open this publication in new window or tab >>Controlled drug release from gels using surfactant aggregates: II. Vesicles formed from mixtures of amphiphilic drugs and oppositely charged surfactants
2001 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 18, no 11, p. 1585-1591Article in journal (Refereed) Published
Abstract [en]

URPOSE:

The aim of this study was to control the release of charged drugs from gels by adding surfactants that can interact with the drug and polymer matrix.

METHODS:

The in vitro release from gels was measured by using 6-mL gel holders immersed in 250 mL of simulated tear fluid and detecting the ultraviolet absorbance on-line. Gels were characterized by using a controlled rate rheometer, and surfactant aggregates were characterized by using cryo-transmission electron microscopy.

RESULTS:

The diffusion coefficient of alprenolol was 2.8 x 10(-6) cm2/s in a lipophilically modified poly(acrylic acid) gel without surfactants present and 0.14 x 10(-6) cm2/s when formulated with 1% sodium dodecyl sulfate. For fluvastatin, the diffusion coefficient changed from 3.0 x 10(-6) cm2/s to 0.07 x 10(-6) cm2/s in the presence of 0.2% benzyldimethyldodecyl-ammonium bromide. Alprenolol, betaxolol, metoprolol, diphenhydramine, and fluvastatin formed vesicles with oppositely charged surfactants in physiologic salt conditions.

CONCLUSIONS:

In this article we show that it is feasible to control the release of charged drugs from gels by using surfactants. Vesicles are generally formed when surface active drugs are mixed with oppositely charged surfactants in physiologic conditions. The strongest effects on the release rate are seen for lipophilically modified polymer gels in which the drug and the oppositely charged surfactant form vesicles, but systems with micelles also give a slower release.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89521 (URN)10.1023/A:1013086632302 (DOI)11758767 (PubMedID)
Available from: 2001-11-15 Created: 2001-11-15 Last updated: 2017-12-14Bibliographically approved
5. Controlled Drug Release from Gels Using Lipophilic Interactions of Charged Substances with Surfactants and Polymers
Open this publication in new window or tab >>Controlled Drug Release from Gels Using Lipophilic Interactions of Charged Substances with Surfactants and Polymers
2002 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 248, no 1, p. 194-200Article in journal (Refereed) Published
Abstract [en]

The aim of this article was to study interactions between different gel forming polymers and amphiphilic drugs and surfactants with the intention of finding interactions that can be used for designing controlled release formulations. The release from gels was measured by detecting the UV-absorbance of drugs released from 6 mL gel into 250 mL release medium in a dissolution bath. The rheological behavior of gels was characterized using a controlled rate rheometer. The diffusion coefficient of alprenolol was 6.3 x 10(-6) cm(2)/s when formulated in a 1% poly(acrylic acid) gel (PAA) and 2.8 x 10(-6) cm(2)/s in a lipophilically modified gel (LM-PAA). The addition of alprenolol to 1% LM-PAA increased the elasticity, G', from 123 to 182 Pa. Increased gel strength was also observed for a number of other amphiphilic drugs. The addition of 1% Brij 58 to LM-PAA decreased the diffusion coefficient of alprenolol to 2.3 x 10(-6) cm(2)/s. It was possible to sustain the release of charged drugs with high log P by adding surfactant micelles. However, the effect was small and only useful for drugs with adequate lipophilicity. The interaction between LM-PAA and amphiphilic drugs could be seen using rheology and was used for designing controlled release gel formulations. In this way surfactants can be avoided, thus decreasing toxicity problems.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89522 (URN)10.1006/jcis.2001.8182 (DOI)16290522 (PubMedID)
Available from: 2001-11-15 Created: 2001-11-15 Last updated: 2017-12-14Bibliographically approved
6. Evaluation of drug release from gels on pig nasal mucosa in a horizontal Ussing chamber
Open this publication in new window or tab >>Evaluation of drug release from gels on pig nasal mucosa in a horizontal Ussing chamber
2002 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 83, no 3, p. 377-388Article in journal (Refereed) Published
Abstract [en]

In this study, controlled release gel formulations containing dihydroalprenolol (DHA), hydrocortisone (HC) or testosterone (TS) in Carbopol 934P (C934) were evaluated using pig nasal mucosa in a horizontal Ussing chamber. The controlled release gel formulations were designed by including DHA in vesicle bilayers formed with sodium dodecyl sulphate (SDS) (1.4 and 36 mM) and by partitioning TS to the core of Brij 58 (B58, 1%) micelles. For comparison, unmodified gels and solutions of the drugs and additives were examined in parallel experiments. The viability and toxicity were evaluated with electrophysiological measurements and light microscopy. The results showed that C934 did not affect the viability of the mucosa and that the rate and profile of the appearance on the receiver side was independent of whether the substances were released from an unmodified gel or an unmodified solution. Continuous electrophysiological measurements made during exposure showed that B58 (1%) and SDS (1.4 mM) inactivated the mucosa, whereas SDS (36 mM) activated it. Investigations made after a 90-min exposure to the formulations showed that all the modified gels had inactivated the mucosa and had negative effects on the morphology. For the TS-B58 (1%) and the DHA-SDS (36 mM) gels, the rate-limiting step in transport was the release from the formulation. The results confirmed that gels from C934 are suitable for nasal administration and also clearly indicated the different degrees of toxicity of the controlled release formulations evaluated in this study. The horizontal Ussing chamber method was a suitable tool for the evaluation of gels for nasal administration.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89523 (URN)10.1016/S0168-3659(02)00209-2 (DOI)12387946 (PubMedID)
Available from: 2001-11-15 Created: 2001-11-15 Last updated: 2017-12-14Bibliographically approved

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