M.F. Serafini

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.

Effect of water-soluble additives on drug release from silicone rubber matrices. II. Sustained release of prednisolone from non-swelling devices

Abstract Multi-week release of 20% loading doses of micronized prednisolone from silicone rubber disks to isotonic pH 7.4 phosphate buffer is shown to be activated by liquid water carriers, such as glycerol. elhylene glycol and polyethylene glycol 200. through a mechanism not involving matrix swelling. Although the release pattern is of the t type. the solely diffusion-controlled mechanism for suspension slabs is ruled out by a dependence of the release “rate” (slope of the t plot) on the disk thickness. The “rate” is also shown to depend on the particular water carrier and water carrier-to-polymer ratio, and on the drug load and particle size.

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.

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.

A new method for determining the diffusion coefficient of drugs in semisolid vehicles from release data

Abstract Experimental data on release of benzocaine from a series of hydrophilic gels were used for the evaluation of a new method for determining the diffusion coefficient of drugs in semisolid vehicles. The values of D, the drug diffusivity in the vehicle, and of R, the diffusional resistance of the membrane interposed between releasing and receiving phase, resulted from a fit of the experimental release data to theoretical data generated by numerical analysis of a vehicle-membrane controlled diffusional model. Comparison of the computed D (and R) values with values obtained by different routes, or with literature data, showed the method to be conducive to rather accurate estimates of these parameters, in cases where the requirements of the theoretical model were fulfilled by the experimental system. The results are discussed in terms of validity, accuracy and applicability of the proposed method. Results obtained from systems not complying with the diffusional model are also discussed and evaluated. The computations were executed with the aid of an IBM 370/168 computer.

A study of controlled-release systems for progesterone based on crosslinked poly(ethylene oxides)

Abstract The characteristics of suspension-type matrices for the controlled release of hydrophobic drugs, based on crosslinked poly(ethylene oxides) (cr-PEO) have been investigated using progesterone (PGT) as a model drug. The drug amounts that can be reproducibly loaded in polymer by an impregnation technique are limited by crystalline drug expulsion from the matrix during solvent evaporation, depending on the degree of crosslinking of the polymer. cr-PEO of crosslinking degrees adequate to confer the required mechanical stability on the swollen matrix can be loaded with no more than 8–10% drug. A polymer with low crosslinking degree was loaded with up to 39% drug, but showed poor mechanical properties in its fully swollen state. The thermal behavior of the PGT-cr-PEO systems, as assessed by DSC, indicates drug-polymer interactions typical of monotectic dispersions. PGT release from cylindrical cr-PEO matrices is not influenced by the matrix swelling kinetics and is consistent with a model assuming that drug diffusion in the polymer phase of the fully swollen hydrogel is the rate-controlling factor. A cr-PEO of comparatively low degree of crosslinking was shown to match uncrosslinked polyethylene glycols with respect to the ability to enhance the dissolution rate of high PGT loads.

Evaluation of the solution impregnation method for loading drugs into suspension-type polymer matrices: a study of factors determining the patterns of solid drug distribution in matrix and drug release from matrix

Abstract Several implications of using the solution impregnation method for loading drugs into suspension-type polymer matrices are discussed. The effects of impregnation solvent volatility drug physicochemical nature and polymer composition gradients on the ultimate solid drug distribution in the dried matrix and the drug release pattern generated by such a distribution are investigated. Polydimethylsiloxane (PDS) elastomer is used as the basic matrix material. In some instances a hydrophilic layer is created at the surface of the PDS matrix by means of a gradient interpenetrating network (IPN) of poly(2-hydroxyethyl methacrylate) (p-HEMA). Progesterone (PGT) and benzocaine (BZC) are used as model drugs. When a volatile solvent and a highly soluble drug in solvent are used to load the unmodified PDS polymer, drug accumulation in matrix core and a surface layer free of solid drug result from matrix drying. Such a distribution pattern reduces the time dependence of the drug release rate with respect to the uniform distribution. A similar drug distribution is also obtained with the IPN-modified matrix when it is loaded by a PGT-chloroform impregnation solution. The drug release pattern in this case is nearly of zero order as the hydrophilic layer comprises a rate-limiting barrier to PGT escape. On the other hand BZC distributes mainly in the IPN-modified surface layer owing to its high affinity for p-HEMA, and therefore, the drug release pattern in this case is characterized by a strong burst effect.