E. Nannipieri

Silicone microspheres for pH-controlled gastrointestinal drug delivery

Silicone microspheres containing pH-sensitive hydrogels are prepared, characterized and evaluated for their potential pH-controlled gastrointestinal (GI) drug delivery. The pH-sensitive hydrogels are semi-interpenetrating polymer networks (semi-IPN(s)) made of varying proportions of poly(methacrylic acid-co-methylmethacrylate) (Eudragit (EUD) L100 or EUD S100) and crosslinked polyethylene glycol 8000 (P8000C). Up to 35 wt% hydrogel particles of mean volume diameters from 89 to 123 microm, medicated with 15 wt% prednisolone (PDN), are encapsulated, with 100% efficiency, into morphologically acceptable silicone microspheres in the 500-1000 microm size range, by a modified emulsion vulcanization method. Microspheres are eluted for 9 h with isotonic fluids at pH values increasing from 1.2 to 7.4, to simulate transit across the GI regions. PDN release depends on dissolution medium pH and on hydrogel composition, which determines hydrogel pH-sensitivity. With the P8000C-EUD L100 (1:2) semi-IPN, the release shows a marked peak at pH 6.8. The P8000C-EUD S100 (1:2) semi-IPN causes a gastroprotection and an almost uniform distribution of released drug between media at pH 6.8 and 7.4. With the P8000C-EUD S100 (1:1) semi-IPN, the dose fraction released to gastric fluid increases to match the values for the media at pH 6.8 and 7.4. With the pH-insensitive, highly swelling, P8000C, the largest dose fraction is released to the gastric medium and release is of Fickian type. With semi-IPNs, release depends weakly on the buffer molarity of the dissolution medium, a reduction from 0.13 to 0.032 of which renders the release rate to the media at pH 6.8 and 7. 4 more uniform.

In vitro evaluation of a pH-sensitive hydrogel for control of GI drug delivery from silicone-based matrices

Abstract The release of drugs having very different aqueous solubilities and partitioning properties, such as salicylamide (SAM), nicotinamide (NAM), clonidine·HCl (CHC) and prednisolone (PDN), from 1 mm thick silicone discs containing, in dispersion, around 35 wt% medicated granules of a pH-sensitive hydrogel, is studied in vitro. The hydrogel is a poly(acrylic acid) (PAA):poly(ethylene oxide) interpenetrating polymer network (IPN). The matrices are eluted with simulated GI fluids, i.e., with a medium of pH 1.2 for 2 h, followed by a medium of pH 6.8 for 2 h, followed by a medium of pH 7.4 for 5 h. The release rate pattern is always bimodal and is determined by the pH-dependent swelling of the IPN granules in matrix. In simulated gastric fluid (SGF) the IPN swelling degree is low and the release is limited to an initial burst, followed by a rapid decline. In simulated intestinal fluid (SIF), PAA in the IPN becomes ionized, the IPN swelling degree increases and the release rate rises to a second maximum. The drug fraction released is always preponderant in SIF compared to SGF. The matrix swelling and drug release rates are influenced by the granule size. With a loading dose of 5 wt% in IPN granules in the 355–425 μm size range, SAM, NAM and PDN show the same release rates in SIF. Differences arise when the load is raised to 20 wt% and/or the granule size range is reduced to 105–250 μm. CHC shows an ionic interaction with PAA in the IPN, which limits the release rate in SIF. The release of drugs not ionically interacting with PAA is virtually uninfluenced by ample variations in osmolality, ionic strength and buffer molarity of dissolution medium.

Vehicle effects on in vitro skin permeation of and stratum corneum affinity for model drugs caffeine and testosterone

The effects of Labrasol (LBS) (glycolysed ethoxylated C8/C10 glycerides), Labrafil (LBF) (glycolysed ethoxylated glycerides), Transcutol (TSC) (diethylene glycol monoethyl ether) and DPPG (propylene glycol dipelargonate) on the flux across excised human skin of the lipophilic testosterone (TST) and the hydrophilic caffeine (CAF) and on the affinity of the human stratum corneum for these drugs are compared taking propylene glycol (PG) and liquid petrolatum (LP) as reference vehicles. DPPG and LBF enhance CAF flux relative to PG while LBS and TSC increase the stratum corneum affinity for TST relative to LP. However, the materials tested enhance neither the flux of nor the stratum corneum affinity for both drugs with respect to either reference. On the other hand, a saturated solution of DPPG in PG enhances both properties for both drugs relative to PG. Such effects are ascribed to the ability of DPPG to interact with the lipid bilayers and to that of PG to promote DPPG penetration into stratum corneum and to create interaction sites in such a tissue.

Drug release from silicone elastomer through controlled polymer cracking: an extension to macromolecular drugs

Abstract An attempt to promote macromolecule release at controlled rates from a polydimethylsiloxane elastomer (Silastic Q7-4840) through osmotically induced osmotically active granules in the 40–106,106–150 or 150–212 μm size range, composed of bovine serum albumin (BSA) and sodium chloride in a 35:65 or 70:30 w/w ratio. The latter granule composition was found to be unsuitable, due to an inadequate level of osmotic agent. With the 35:65 w/w BSA-NaCl ratio in granules protein release to normal saline is of zero-order in the matrix swelling stage. The stationary release rate and time scale are modulated through matrix geometry and granule load and size. With disk-shaped devices and 106–150 or 150–212 μm granule size the release rate and granule load are linked by a log-log correlation. The release pattern is determined by the rate of polymer cracking. The solutes are carried through cracks by a composite convective-diffusive flux.

Polyoxyethylene-poly(methacrylic acid-co-methyl methacrylate) compounds for site-specific peroral delivery.

pH-sensitive interpolymer interactions between high molecular weight polyoxyethylene (POE) and poly(methacrylic acid-co-methyl methacrylate) (Eudragit (EUD) L100 or S100) are evidenced and exploited to prepare, from either POE-EUD coevaporates or POE+EUD physical mixtures, both in the 1:1 wt. ratio, compressed matrix tablets, potentially able to deliver the model drug, prednisolone, to sites in the GI tract characterized by specific pHs, such as the jejunum or the ileum. With these devices, drug release is inhibited at pHs lower than the threshold of EUD ionization, whereas at pHs exceeding such a threshold, the matrix undergoes a gradual erosion, which controls the release. A post-compression exposure of tablets to the vapors of appropriate solvents realizes the necessary compaction of matrices, in fact, a high compression force (3 ton) is insufficient, per se, to prevent matrix disintegration in the dissolution medium, whereas such a disintegration is prevented by the treatment with solvent vapors, even with a low compression force (0.3 ton). With the POE+EUD physical mixtures, the exposure to solvent vapors promotes the formation of a layer of POE-EUD complex at the interfaces of the POE and EUD particles in matrix, which inhibits release at pHs lower than that designed for delivery. Both POE and EUD concur to determine the properties of the POE-EUD complex relevant to drug release, indeed, EUD ionization, which elicits matrix erosion and drug release, is favored by the hydrophilic POE. In fact, matrices based on plain EUD exhibit a comparatively low release rate, more suited to an extended delivery to the colon than to a specific delivery to the ileum. Details of the release mechanism are discussed.

Bile acids as enhancers of steroid penetration through excised hairless mouse skin

Abstract Excised hairless mouse skin (EHMS) is used to evaluate the potential of sodium choleate (NaCOL), an ox bile extract containing the sodium salts of taurocholic, glycoeolic, desoxycholic and cholic acids, and of the free choleic acids (HCOL) to enhance the transcutaneous penetration of progesterone (PGT) and prednisolone (PDN). EHMS is pretreated with aqueous dispersions of the enhancers, then the steroids are allowed to permeate through the pretreated EHMS from normal saline under occluded conditions. NaCOL is ineffective whereas HCOL produces structural modifications of the stratum corneum, resulting in increased skin permeability of both steroids. The chloroform-soluble components of HCOL interact strongly with stratum corneum lipids, as demonstrated by differential scanning calorimetry, thus facilitating PGT penetration. The chloroform-insoluble components of HCOL interact with more polar structures of stratum corneum, thereby promoting PDN transport. The data also suggest the existence of a parallel drug co-transport mechanism by the more lipophilic HCOL components.

Enhancement effects in the permeation of Alprazolam through hairless mouse skin

Abstract Alprazolam (ALP) is an anxiolytic, antidepressant agent, having suitable features for the development of a transdermal medication. The objectives of this preliminary study were to determine: (a) whether ALP is absorbed in vitro through hairless mouse skin; (b) whether it is metabolized during diffusion, and (c) the influence of some chemicals on ALP penetration through skin. ALP permeates through hairless mouse skin in vitro. No degradation product of the drug resulted during skin permeation experiments, therefore, ALP was assumed to diffuse unchanged across the skin. Oleic acid (OLA), linoleic acid (LNA), linoleic acid diethanolamide (LNDA), coconut fatty acid diethanolamide (CNDA), lauric acid diethanolamide (LRDA), bis(2-hydroxuethyl)cocamine (HECA) and isopropyl lanolate (IPL) were evaluated with respect to their skin-permeation enhancing effect either as neat solvents or combined with propylene glycol (PG). All the vehicles excepting IPL and PG were more effective than OLA in enhancing transdermal absorption of ALP. The most effective was HECA followed by LNDA, CNDA and LNA/PG (8.5:1.5, w/w). The effects of skin pretreatment with HECA, LNA, LNDA and CNDA on the percutaneous absorption of ALP from a drug suspension in IPL were also investigated. For all the pretreatment vehicles ALP flux from IPL through pretreated skin was greater than that from IPL or OLA through untreated skin. In order to facilitate the interpretation of the absorption results, the stratum corneum/water, whole skin/water and n -octanol/water partition coefficients of the drug were determined.

Electrical impedance changes and water content in O/W emulsions during evaporation

A method for measuring the variation of electrical impedance (Z) of thin layers (0.1 mm) of O/W emulsions during evaporation in a controlled environment is presented. The evaporation of an emulsion base (A) either as such and containing 1% glycerin (B) or 1% sodium pyrrolidonecarboxylate (C) was investigated for 120 min at constant air temperature (25°C) and relative humidity (55%). The measured impedance of the emulsion layers increased by three orders of magnitude during the evaporation cycles. The relationship between impedance and water content of the evaporating emulsion layers was investigated. Each emulsion showed a complex linear relationship between log Z and water content, the relationship being represented by two (three, for emulsion A) linear portions in the graph. Plots of water content vs. time, temperature vs. time and rate of water loss vs. water content of the emulsion layers are presented. The data appear to indicate that evaporation proceeds via distinct stages, whose correspondence to different mechanisms of water evaporation is discussed. The potentiality of the present method for water analysis, and for investigating structural changes in emulsions during evaporation, is also discussed.

Evaluation of a silicone based matrix containing a crosslinked polyethylene glycol as a controlled drug delivery system for potential oral application

Abstract A silicone based matrix containing dispersed medicated granules of a crosslinked polyethylene glycol with high swelling capacity is evaluated for its potential to release in vitro substantial fractions of drugs of different solubilities within 6 hours at controlled rates. Papaverine- HCl, clonidine- HCl and salicylamide are the model drugs. With a matrix shape of a 0.1-cm thick disc, a weight fraction of granules in matrix of around 35% and an appropriate granule size, dose fractions of around 80% are released with √t-type kinetics. The particular drug type and the drug content in granules, within the range of 5–20%, are without influence on the pattern and rate of fractional release. The release pattern depends on the pH of the elution medium, but the pH effects can be offset by properly controlling the granule size. Thus, the above features of release are obtained with normal saline as the elution medium, using granules of 354–425 μm, or with a medium whose pH is gradually increased from 1.2 to 7.4 to simulate the conditions of the GI tract, using granules of 105–250 μm. Drug release is initially controlled by the rate of increase of the number and size of interconnections among granules in course of swelling. Drug diffusion in the interconnected hydrogel gradually takes control of release.

Influence of drug-surfactant and skin-surf actant interactions on percutaneous absorption of two model compounds from ointment bases in vitro

Abstract The role of either of two surfactants, sorbitan monooleate (HLB 4.3) and polyoxyethylene n -lauryl ether (HLB 12.8), in mass transfer of two model drugs through human epidermis from oleaginous ointments, has been investigated. The two drugs, benzocaine and 2-ethylhexyl p -dimethylaminobenzoate, possess different lipophilic properties. Both the thermodynamic activity coefficient changes and the apparent permeability changes produced by surfactant addition to the ointments are independently assessed, thus making it possible to separate the thermodynamic effects of the surfactants from their permeability-enhancing effects mediated through a direct action on the physicochemical properties of the biological membrane. The surfactants appear to interact with both the drugs and the skin in degrees which are dependent on the polarity of the surfactant and the drug. Although each of the surfactants interacts with human epidermis in a way and to an extent independent of the penetrant nature, nevertheless they appear to be rather specific in their action, i.e. they have shown different effects on skin permeability to drugs showing different polarity.