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Biomedical subjects

B C Lippold

Publications and source records attributed to B C Lippold.

At least 19 recordsLinked to original sources
PubMed2003

Investigations on the predictability of the formation of glassy solid solutions of drugs in sugar alcohols.

A prerequisite for the formation of glassy solid solutions prepared by the melting method is the miscibility of the respective drug and the carrier in the molten state. As could be shown experimentally, all investigated drug/sugar alcohol combinations miscible in the molten state form to some extent glassy solid solutions, dependent on their tendency to recrystallize during preparation. Therefore, the present study focuses on the evaluation of factors that govern the miscibility of molten drugs and sugar alcohols as carriers. In this context, solubility parameters are discussed as a means of predicting miscibility in comparison to a new approach, using calculated interaction parameters derived from molecular dynamics (MD) studies. There is evidence that a Coulomb interaction term C(SR), comprising short-range electrostatic interactions and hydrogen bonding energy is essential for the miscibility of drug and carrier in the molten state. To relate C(SR) to the molecular volume, a non-dimensional parameter P(i) is defined. For this parameter, a limiting value for miscibility exists. Contrary, calculated solubility parameter differences between drug and sugar alcohol in the range of 8-15 MPa(1/2) are not suitable for a prediction of miscibility or immiscibility, since the mixtures deviate from regular solution behavior. In irregular mixtures of drugs and sugar alcohols, an excess entropy and the formation of hydrogen bonds between unlike molecules favor miscibility, that cannot be predicted by regular solution theory.

Glass↗
PubMed2001

Polymer particle erosion controlling drug release. I. Factors influencing drug release and characterization of the release mechanism.

The present study deals with controlled drug delivery from hydrocolloid tablets by polymer particle erosion. The influence of excipients and formulation factors on the dissolution behaviour of the methyl hydroxyethyl cellulose (MHEC)-tablets is investigated. Linear drug release with low susceptibility to hydrodynamic stress is obtained. The use of drugs with higher solubility leads to a slight acceleration of the release due to the contribution of diffusion to the release process. Higher drug loading and consequently lower polymer content expedites dissolution as well as changes in the tablets' geometry resulting in enlarged release surfaces. Furthermore, alterations of the composition of the dissolution medium affect drug release. However, neither viscosity grade nor the particle size of the polymer or compaction pressure has a marked impact on the dissolution. Investigations to clarify the mechanism of polymer particle erosion include erosion studies and the comparison of different batches of MHEC, of products from different manufacturers and of fibrous trial products. There is evidence that the insoluble fibres within the water soluble MHEC are responsible for the occurrence of polymer particle erosion by disturbing swelling and formation of a thick coherent gel layer and thus, causing erosion of the hydrocolloid tablet with synchronous drug release.

Analgesics, Non-Narcotic↗
PubMed2001

An easy producible new oral hydrocolloid drug delivery system with a late burst in the release profile.

One of the main drawbacks of hydrocolloid matrices as oral controlled drug delivery systems is the often observed decreasing rate of drug release at the end of the release process. This study describes a new pH-controlled hydrocolloid drug delivery system consisting of a neutral cellulose ether as basis polymer and enteric coating materials as additives. The new dosage form is able to accelerate the drug release at a predetermined pH. In a typical example, methylhydroxy ethylcellulose, MHEC 10000 B, was used as the basis polymer and hydroxypropyl methylcellulose acetate succinate, HPMCAS HF, as release modifier. The new delivery system is characterized by its homogeneous structure and easy production by direct compression of the components. The acceleration is well reproducible. Furthermore the new formulation shows high stability against hydrodynamic stress and tolerates ionic strengths up to 0.25 without any significant changes in the release profile. As mechanism of the final burst at pH values >5.7, enforced erosion of the gel layer surrounding the tablet core, could be identified.

Administration, Oral↗
PubMed2001

Film formation, reproducibility of production and curing with respect to release stability of functional coatings from aqueous polymer dispersions.

The formation of film coatings from aqueous polymer dispersions is a complex process, highly dependent on additives and process parameters. Release instability of modified release coatings from aqueous polymer dispersions is a frequently described problem that hinders the general application of such dispersions. However, if some important prerequisites are fulfilled, storage stability should be achievable. Most important are: (a) The appropriate plasticizing time has to be considered, incorporating sparingly soluble plasticizers in the dispersion. (b) Necessary pore formers increase the permeability of the coating to a desired and constant extent only if they are compatible with the polymer. (c) Coating in the fluidized bed at or slightly above the minimum film forming temperature may lead to only incomplete film formation. Curing at higher temperatures improves the polymer particles coalescence to a physically stable state. Other stability aspects such as physical and chemical aging, migration of plasticizers and drugs and incompatibilities are also discussed.

Chemical Phenomena↗
PubMed2001

Control and stability of drug release from diffusion pellets coated with the aqueous quaternary polymethacrylate dispersion Eudragit RS 30 D.

The addition within compatibility limits of the pore formers hydroxypropyl methylcellulose (HPMC) and hydroxy ethylcellulose (HEC) to coatings of the quaternary polymethacrylate dispersion Eudragit RS 30 D enables drug release to be controlled without problems. 20 and 15%, respectively, of these pore formers are suitable for release within 8 h of theophylline from pellets with a coating thickness of about 30 microns. A 10% addition of plasticizer, water soluble triethyl citrate (TEC) or water insoluble dibutyl phthalate (DBP), lowers the minimum film forming temperature (MFT) from 48 to 17 and 26 degrees C, respectively. The MFT is scarcely influenced by the pore formers. However, the plasticizers may modify the effect of the pore formers: HPMC is more effective in the presence of DBP. In spite of the preparation of the coatings at a bed temperature about 20 degrees C above MFT, the release from the diffusion pellets is not stable during storage. Only curing in an oven or in the fluidized bed up to a certain limiting release rate at 80 degrees C for 1 h results in stable products. Increased relative humidity allows reduction of the curing temperature. The water soluble additives polyoxy ethylene (PEG) and polyvinyl pyrrolidone (PVP) and insoluble additives are ineffective as pore formers.

Acrylic Resins↗
PubMed2000

A new oral erosion controlled drug delivery system with a late burst in the release profile.

A new oral erosion controlled drug delivery system on the basis of polyvinyl alcohols with a late burst in the release profile is developed. This late burst occurs after addition of sparingly soluble substances, either excipients like carboxylic acids and neutral cellulose or drugs like theophylline and theobromine. The onset time between 4 and 12 h and the extent of the burst between 20 and 60% are well reproducible and depend on the type of the used additive and the particle size of the basic polymer. For dissociating additives like glutamic acid, the pH within the swelling and eroding hydrocolloid tablet is decisive, differing from the pH of the dissolution medium and controlling the release process. Only polyvinyl alcohols with a ratio of viscosity number to degree of hydrolysis in the range from 2.3 to 3 exhibit acceleration of release in the final phase. As mechanism of the burst, enforced erosion of the gel layer, surrounding the tablet core, could be identified.

Administration, Oral↗
PubMed2000

Prediction of the efficacy of cutaneously applied nonsteroidal anti-inflammatory drugs from a lipophilic vehicle.

The maximum cutaneous fluxes of 12 nonsteroidal anti-inflammatory drugs (NSAIDs), determined in a preceding study from the lipophilic vehicle light mineral oil in vivo on 24 healthy volunteers, were related to data concerning their intrinsic activities. From the multiplication of the relative intrinsic activities with the relative maximum fluxes, both related to indometacin (CAS 53-86-1) as standard, the percutaneous activities result as parameters for the prediction of the efficacy of cutaneous preparations with NSAIDs. According to the results of the calculations, the percutaneous activities of ibuprofen (CAS 15687-27-1) and nabumetone (CAS 42924-53-8) from lipophilic vehicles are remarkable because of their very high maximum fluxes. NSAIDs with still high percutaneous activities are ketoprofen (CAS 22071-15-4), naproxen (CAS 22204-53-1), piroxicam (CAS 36322-90-4) and diclofenac (CAS 15307-86-5). In contrast, the systemically highly effective NSAIDs indometacin and acemetacin (CAS 53164-05-9) show rather low percutaneous activities, when applied in lipophilic vehicles. Especially nabumeton and also tenoxicam (CAS 59804-37-4), both not yet commercially used cutaneously, can be recommended for lipophilic skin preparations.

Administration, Topical↗
PubMed1999

[Concept of control of galenic properties in oral administration of drugs].

The pharmaceutical and biopharmaceutical development of drug preparations comprehends the transformation of a drug in an applicable drug preparation with optimal efficacy, safety and acceptance. Thus, a drug delivery system has to be developed that controls the onset, the duration and the intensity of the expected effect. Depending on the specific drug properties and to the special objectives different controlling principles have to be selected. These are for example delayed release (salivaresistance, gastroresistance), slow release, release in distinct regions of the gastrointestinal tract and accelerated release.

Administration, Oral↗
PubMed1999

Aqueous ethyl cellulose dispersions containing plasticizers of different water solubility and hydroxypropyl methylcellulose as coating material for diffusion pellets. I. Drug release rates from coated pellets.

The present work investigates release mechanisms of theophylline pellets coated with an aqueous ethyl cellulose (EC) dispersion containing plasticizers and hydroxypropyl methylcellulose (HPMC) as a water soluble pore former. Three different drug release mechanisms from coated pellets can be determined as a function of the water solubility of the plasticizers and the ionic strength of the release medium. Coated pellets with the addition of more hydrophilic plasticizers such as triethyl citrate (TEC) or diethyl phthalate (DEP) show an approximate zero-order-release rate. In contrast, two-phase release profiles can be observed from pellets coated with dispersions containing hardly soluble plasticizers such as dibutyl phthalate (DBP) or dibutyl sebacate (DBS). Only in a release medium of high ionic strength the water soluble pore former will remain in the coating. Thus the drug diffuses through a hydrated swollen membrane containing EC, HPMC and insoluble plasticizer. The release mechanisms depend on the glass transition temperature of the ethyl cellulose and therefore on the migration of the plasticizers and the pore former. This was shown by investigation of the migration of the additives and the influence of the temperature of the release medium on the release. Additionally, the study investigates the effect of curing and storage conditions of coated pellets on the drug release rate.

Cellulose↗
PubMed1999

Do local anesthetics have an influence on the percutaneous penetration of a model corticosteroid? An in vivo study using the vasoconstrictor assay.

Local anesthetics may exert nonspecific interactions with membrane components which can affect drug permeability. To investigate pharmacodynamically whether these membrane interactions lead to penetration enhancement of the coadministered model drug betamethasone-17-benzoate through human skin, the vasoconstrictor assay was used. Information on the penetration-enhancing properties of local anesthetic-containing vehicles compared to a plain standard were obtained from activity-response curves, where the enhancement factor was determined from the horizontal distance between the standard and a test in the linear range of the curves. The local anesthetics are able to enhance drug penetration through human skin to a different extent with lidocaine being the most efficient enhancer. An increase in the drug solubility and the diffusion coefficient in the stratum corneum due to membrane fluidization are possible mechanisms of action.

Adolescent↗
PubMed1999

Drug release from diffusion pellets coated with the aqueous ethyl cellulose dispersion Aquacoat ECD-30 and 20% dibutyl sebacate as plasticizer: partition mechanism and pore diffusion.

The release of the hydrophilic etofylline and the lipophilic propyphenazone (octanol/water partition coefficient PC = 0.35 and 119, respectively) from diffusion pellets coated with the aqueous ethyl cellulose dispersion Aquacoat ECD-30 and 20% dibutyl sebacate (DBS) as plasticizer is investigated as a function of pH. The relatively slow release is not constant, due to the broad distribution of different release rates within the pellet population and the non-linearity of the release of each diffusion pellet itself. The release proceeds according to a partition mechanism at a pH < 6. The partition mechanism is not influenced by the osmotic pressure difference between the release medium and the saturated solution within the diffusion pellets. The diffusion coefficients of different drugs in the plasticized coating are in the range 1 to 5 x 10(-8) cm2/s. At a of pH > 6 an additional hydrophilic pathway without partition exists if the diffusion pellets did not have any contact with an acidic medium. This is due to the strongly increased water uptake of more than 20% by the coatings as a consequence of the dissociation of carboxyl groups in the ethyl cellulose.

Cellulose↗
PubMed1999

Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl-cellulose as coating material for diffusion pellets II: properties of sprayed films.

This study investigates the properties of sprayed films prepared from aqueous ethyl cellulose dispersions (ECD) containing hydroxypropyl methylcellulose (HPMC) and plasticizers of different water solubility in order to clarify the drug release mechanisms of pellets coated with the respective material. It is of special interest to measure the migration of the water soluble components as well as the physical properties of the swollen ethyl cellulose film. Swelling experiments with sprayed films in 0.1 N-HCl at 37 degrees C show that fairly water soluble plasticizers and the pore forming agent (HPMC) migrated rapidly and almost completely out of the films. The water insoluble plasticizers remain predominantly in the film and the migration rate of HPMC is reduced in a release medium of high ionic strength. The glass transition temperature (T(g)) and the softening temperature (T(s)) of these films after swelling are dependent on the water solubility of the plasticizer. The T(g) of ECD films plasticized with triethyl citrate is above the swelling temperature of 37 degrees C after migration of the plasticizer, transforming the polymer in the glassy state. In contrast, dibutyl phthalate-containing ECD films demonstrate a T(g) below the swelling temperature, leaving the polymer in the rubbery state. The mechanical properties of dry and wet films are studied as a function of the state of curing of the films and of the swelling temperature. On contact with water, a pronounced shrinkage of ECD/HPMC films plasticized with water insoluble plasticizers is observed. All these results are used to explain the different drug release mechanisms of the coated pellets and to enable the prediction and optimization of drug release-rates from coated pellets.

Algorithms↗
PubMed1999

Skin penetration of nonsteroidal antiinflammatory drugs out of a lipophilic vehicle: influence of the viable epidermis.

The skin penetration of 10 nonsteroidal antiinflammatory drugs (NSAIDs) was investigated after application in the lipophilic vehicle light mineral oil. The skin permeabilities and maximum fluxes, which were calculated from the concentration decreases of the applied solutions in the steady state phases, were correlated with physicochemical parameters, mainly the vehicle solubilities and the partition coefficients of the model drugs according to the Fickian diffusion laws. The objective of the study was to characterize the barrier function of the stratum corneum and the viable epidermis and to predict their influences on the skin permeabilities and the maximum fluxes of the NSAIDs by model equations. The permeability of the human skin for NSAIDs applied in a lipophilic vehicle is a function of their hydrophilicity, while the maximum flux is primarily dependent on their vehicle solubilities. The viable epidermis was found to represent the decisive resistance to the drug transport.

Administration, Topical↗
PubMed1998

Percutaneous penetration enhancement and its quantification.

True penetration enhancing effects resulting from structural alterations of the barrier stratum corneum manifest themselves in an increase of the drug diffusion coefficient DB and/or of the drug solubility in the barrier csB. The quantification of enhancing effects on drug penetration is possible either by the direct determination of the drug fluxes or by an indirect determination through the measurement of the pharmacodynamic response. In both cases the thermodynamic drug activity has to be considered. In the case of pharmacodynamic measurements, enhancing effects may be determined from the horizontal distance of activity-response lines obtained without and with enhancer, respectively, i.e. the quotient of the drug concentrations that induce the same effect. The activity-standardized bioavailability factors fa obtained from the horizontal distances correspond to the enhancer-induced relative changes in the permeabilities PB, or more exactly in the product DB X csB. On the other hand, the vertical distance between the activity-response lines, i.e. the differences in the drug response after application of preparations with equal (even maximum) thermodynamic drug activities may be used to quantify penetration enhancing effects.

Administration, Topical↗
PubMed1998

Accumulation of sunscreens and other compounds in keratinous substrates.

Several cosmetic ingredients, especially sunscreens, should be substantive, which means they are to be adsorbed to specific binding sites within the upper skin layers, particularly keratinized structures of the stratum corneum, and thus show resistance to washing off. We investigated the affinity of 10 non-ionic compounds, among these UV-absorbing chemicals, antioxidants, antimicrobial compounds and a repellent to animal keratin and human callus. In each case a linear relationship between the drug amount, which has accumulated in the respective keratin, and the remaining free concentration of the applied solution could be established. Moreover, drug affinities to keratinous substrates are in direct proportion to the octanol/vehicle partition coefficients, pointing to the fact, that drug enrichment in keratinic substrates is clearly governed by lipophilicity, while specific adsorption, i.e. genuine substantivity, does not seem to occur. After application of a saturated solution non-ionic compounds with a pronounced keratin/vehicle partition coefficient will build up the highest concentration within the stratum corneum. If these compounds show, at the same time, a high solubility in the vehicle, they will penetrate the skin most easily. The used callous tissue seems to be a suitable substrate to simulate and quantify solute uptake into human skin.

Animals↗
PubMed1997

In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: prediction of the penetration rate of antimycotics through the nail plate and their efficacy.

In contrast to the partition coefficient octanol/water the molecular size of penetrating drugs has a noticeable influence on the permeability of the human nail plate and a keratin membrane from bovine hooves. The relationship between permeability and molecular weight is founded on well-established theories. The correlation between the permeability of the nail plate and that of the hoof membrane allows a prediction of the nail permeability after determination of the drug penetration through the hoof membrane. The maximum flux of ten antimycotics (amorolfine, bifonazole, ciclopirox, clotrimazole, econazole, griseofulvin, ketoconazole, naftifine, nystatin and tolnaftate) through the nail plate was predicted on the basis of their penetration rates through the hoof membrane and their water solubilities. An efficacy coefficient against onychomycoses was calculated from the maximum flux and the minimum inhibitory concentration. Accordingly, amorolfine, ciclopirox, econazole and naftifine are expected to be especially effective against dermatophytes, whereas in the case of an infection with yeasts only, amorolfine and ciclopirox are promising.

Animals↗