In vivo research following ingesting of commercially available Lactobacillus tablets, which contain about 2X10⁶ cfu/tablet of Lactobacillus acidophilus and Lactobacillus bulgaricus cells in a dose of four tablets daily, showed serum lipoprotein concentrations did not change significantly. In order to increase the number of viable Lactobacillus bacteria after challenging in low pH solution (gastric fluid), enteric coating polymer was applied over dried calcium alginate beads containing Lactobacillus. Survival of Lactobacillus bacteria was generally higher from freeze dried calcium alginate beads compared to vacuum dried products. However, after pretreatment with simulated gastric fluid (pH = 1.5) for 2 hours, only the coated products from vacuum drying showed promising results. Lactobacillus bacteria were fully protected against gastric pH after formulating the bacteria inside mini-tablets which were coated with Eudragit L30D, an enteric coating polymer. Alginic acids are naturally occurring substances found only in the brown seaweeds. Alginic acid salts formed with most di-, and polyvalent metals are insoluble in water. The most common application of alginate precipitation in drug product formulation is based on insolubilization of alginate by addition of calcium salt. By altering the composition of calcium alginate, drug loading, enteric coating thickness, and sustained release coating thickness, the lag time for drug dissolution can be controlled. This formulation research provides oral dosage form design for targeted delivery of drug to any desired site in the gastrointestinal tract. Examples of site specific targeted delivery are given for Lactobacillus bacteria, ibuprofen, sulfasalazine, and 5-aminosalicylic acid. / Graduation date: 1991

Dry powder coating of pharmaceutical dosage forms has been investigated as an alternative method to commonly used liquid based coating techniques. Eudragit[trademark] L 100-55 and Eudragit[trademark] L 30 D-55 have been employed in enteric film coatings using aqueous dispersions, organic solutions and compression coating. However, the copolymer has not been investigated in dry powder coating applications. Initially, formulation factors and processing parameters were investigated for the dry powder coating of chlorpheniramine maleate tablets using Eudragit[trademark] L 100-55 as the delayed release polymer. Powder coating was studied as a method to prevent the migration of an ionizable, highly water soluble model drug into the polymeric film during the coating process. Eudragit[trademark] L 100-55 was pre-plasticized with triethyl citrate (TEC) using hot-melt extrusion and subsequently ground into a fine powder. Polyethylene glycol 3350 (PEG 3350) was used as a primer and low melting coating excipient to enhance coating powder adhesion and to improve film formation. The powder coating process was performed in a modified laboratory scale spheronizer. For the dry-powder coating of sodium valproate tablets different subcoating materials were investigated to improve powder adhesion to the substrate and to reduce the level of Eudragit[trademark] L 100-55 required for gastric resistance. PEG 3350 and Methocel[trademark] K4M were incorporated in the Eudragit[trademark] E PO and Eudragit[trademark] RL PO subcoating formulations as pore forming materials. The miscibility of the PEG 3350 and Methocel[trademark] K4M in the film coating was correlated with their ability to function as pore forming agent. The film formation process of thermally cured Eudragit[trademark] L 100-55 dry-powder coatings was characterized. The influence of film additives on relative melt viscosity, surface free energy of the polymer and the mechanical properties of powder-cast films was studied. The influence of Eudragit[trademark] E PO in Eudragit[trademark] L 100-55 film coatings applied by a dry powder coating technique on the drug release mechanism was investigated. Calculation of the Flory-Huggins interaction parameter based on solubility parameters and different analytical techniques demonstrated immiscibility of the copolymers at processing conditions. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. / text

Graduation date: 1998

This dissertation is comprised of four distinct formulation sections, which are described below: A novel solid dosage formulation was investigated for achieving zero-order drug release profile by combining tablet shape design and tablet membrane film coating. Verapmail (model drug) was compressed into hydrophilic matrix tablet cores of flat-faced and bi-convex shape, which were encapsulated with membrane controlling film. The hydrophilic tablet core contained hydroxypropyl methylcellulose (HPMC) 15 LV, pectin, and Avecil��. The membrane film coating solution was comprised of deionized water, Opadry��, Surelease�� and talc. The combination of membrane film coating and tablet shape design was found to influence in vitro verapamil release profile towards the zero-order release demonstrated by the commercial Covera HS�� (Pharmacia). An alternative formulation for the commercial Bactroban�� (Smithkline Beacham) ointment 2% was developed. Both the texture and consistency of the new ointment were comparable to the Bactroban�� ointment. The new and the commercial formulations were found to be equivalent in drug release by the Bauer-Kirby test. Mupirocin remained unstable in the new formulation. Mg����� was added to help stabilize mupirocin and was shown to complex with mupirocin by nuclear magnetic resonance (NMR). The modified formulation including Mg����� however failed to stabilize mupirocin. The stability assay results showed an average of 67.2% mupirocin recovery along with 25.2% degradation products. A generic omeprazole formulation was developed, which was comprised of nonpareil core, omeprazole matrix layer, and an enteric locating layer of ammoniated hydroxypropyl methylcellulose phthalate (HPMCP) 55S. The new formulation was gastro-resistant in protecting against omeprazole degradation for up to 2 h, but failed to dissolve as rapidly as the commercial Prilosec�� (Astra Merk) in simulated intestinal fluid. The addition of expotab�� to the enteric coating layer failed to improve omeprazole dissolution rate. A novel hot-melt coating methodology utilizing direct blending technique has been developed. The processing steps for the direct blending hot-melt coating are: (a) Hot-melt system preparation; (b) Dispersion/dissolution of the active ingredient(s) in the hot-melt system; (c) Pre-heating of the coating substrate; and (d) Cooling and congealing of the hot-melt on substrate surface. Immunogenic effect was observed in mice administered with enteric-coated ragweed pollen extract (RPE) alpha fraction by the hot-melt coating encapsulation with direct blending method. The effect was not shown to be statistically significant. / Graduation date: 2003

The physical stability of guaifenesin in melt-extruded acrylic matrix tablets was investigated. The initial study found that recrystallization was caused by guaifenesin supersaturation in Eudragit[Trademark] L100-55, and that the instability was confined to tablet surfaces. Drug release was not affected by crystal growth as guaifenesin is very water soluble. The addition of a polymer in which guaifenesin showed a higher solubility to the matrix blend decreased recrystallization on storage as supersaturation levels dropped. The second investigation identified heterogeneous nucleation as an additional factor in guaifenesin recrystallization. A quantitative assay showed that talc in matrix tablets accelerated the onset and extent of the recrystallization due to a nucleating effect on guaifenesin. Storage under elevated humidity conditions promoted recrystallization as well, but crystal growth was not correlated with water uptake, which implied a nucleating effect of moisture on guaifenesin. The third study investigated the effect of aqueous film-coating of the matrix tablets to stabilize amorphous guaifenesin using either hypromellose or ethylcellulose as coating polymers. The selection of the coating polymer influenced crystal morphology, and was a major factor in delaying the onset of crystallization, ranging from 1-3 weeks (ethylcellulose film-coatings) to 3-6 months (hypromellose film-coatings). Higher weight gains retarded recrystallization. Factors promoting drug and polymer diffusion, such as long curing times and elevated temperatures during both curing and storage, incomplete film coalescence and high core drug concentrations all resulted in an earlier onset of crystallization. The effects of single-screw extrusion (SSE) and twin-screw extrusion (TSE) of diltiazem hydrochloride and guaifenesin-containing blends in Eudragit[Trademark] L100-55 on drug morphology and dispersion were studied in the fourth project. Guaifenesin solubilized diltiazem hydrochloride, and plasticized Eudragit[Trademark] L100-55. Extrusion temperature influenced the drug morphology in single-screw extrudates, while TSE rendered all formulations amorphous due to higher dispersive mixing capabilities. Drug distribution improved with extrusion temperature and by TSE over SSE. Homogeneous matrices showed the slowest drug release at pH 1.0. Recrystallization was inversely correlated to drug distribution. In conclusion, the physical stability of guaifenesin in hot melt-extruded acrylic matrix tablets was shown to be affected by formulation, processing and post-processing factors. / text

No description available.

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

This dissertation describes the development of a new sustained release formulation of nifedipine. The new formulation was developed by coating commercially available immediate release soft elastic gelatin capsules using a spray coating technique with two different polymeric combinations. Dissolution studies were conducted and showed that controlled release of nifedipine was obtained by increasing the ratio of the water insoluble polymer in the coat and increasing the percent weight gain of the coating. Simulated plasma concentration versus time profiles after administration of 30 mg dose of selected formulations showed a prolonged nifedipine release with concentrations above the minimum effective concentration for up to 12 hours. Bioavailability and bioequivalence of tableted test formulation of verapamil HCL was determined in 8 volunteers and compared to Covera HS® under fed and fasting conditions. The 90% confidence intervals for individual percent ratios of the Cmax, AUC₀₋₅₈ and AUC₀ were not within the range of 80 - 125% in both fed fasted states, suggesting that these formulations are not bioequivalent. the bioavailability of verapamil from the new formulation was higher state but this effect was not statistically significant. Pharmacokinetics of terbinafine administered orally at single doses of 15, 30, 60 and 120 mg were determined in raptors to recommend an appropriate dosing scheduled for terbinafine in the treatment of Aspergillosis. Calculation of steady state trough terbinafine plasma concentration after administration of daily doses of 15 or 30 mg/day showed that 30 mg daily dose of terbinafine administered orally in raptors produces a steady state trough terbinafine plasma concentration above the minimum inhibitory concentration (MIC) of(0.8 1.6) µg/ml against aspregillus fumigatus. From the data, 30 mg per day oral dose of terbinafine should be the recommended dose for treatment of aspergillosis in raptors. Approximate pharmacokinetic linearity of terbinafine was demonstrated for AUC[subscript 0-t] in the dose range of 15 120 mg while non-linearity for Cmax in the same dose range was demonstrated using the power model. / Graduation date: 2005

The thrust of this thesis is to study oral solid dosage formulation using hot melt coating method and to use pharmacokinetic modeling and simulation (PK M&S) as a tool that can help to predict pharmacokinetics of a drug in human and the probability of passing various bioequivalence criteria of the formulation based on the PK of the drug. Hot-melt coating using a new method, direct blending, was performed to create immediate and sustained release formulations (IR and SR). This new method was introduced to offer another choice to produce IR and SR drug delivery formulations using single and double coating layer of waxes onto sugar beads and/or drug loaded pellets. Twelve waxes were applied to coat sugar cores. The harder the wax the slower the drug was released from single coated beads. The wax coating can be deposited up to 28% of the weight of the core bead with 58% drug loading efficiency in the coating The cores were coated with single or double wax layers containing acetaminophen. Carnauba wax coated beads dissolved in approximately 6 hrs releasing 80% of loaded drug. However, when covered with another layer, the drug loaded beads released drug for over 20 hrs. When drug loaded pellets were used as cores, 33-58% drug loading was achieved. Double coated pellets exhibited a near zero order drug release for up to 16 hrs. Hot melt coating by direct blending using waxes is a simple process compared to conventional hot melt coating using coating pan or fluid bed coating machines. It offers an alternative way of making immediate, sustained drug release (IR, SR) and modified release (IR+SR) oral dosage forms of drugs which are stable at high temperature (100°C). The pellet-containing-drug coated formulations provide options when higher drug loading is warranted. It is required by the US Food and Drug Administration (FDA) that a new modified –release (MR) product or identical generic product be regarded as bioequivalent (BE) to the originators reference drug product. However, there are concerns that current regulatory criteria are not sufficient when evaluating bioequivalence (BE) for many MR products, and additional metrics for BE assessment of the products should be applied to ensure therapeutic equivalence. This study used pharmacokinetic modeling and simulation (M&S) to investigate 1) the probability of BE occurring between the MR test and reference products 2) the rates of false positive and true negative of the BE test; and 3) the estimation of the sample size in pivotal BE studies; all of which when partial area under the curves (pAUCs) were applied as additional BE criteria. Reference data of two MR forms of methylphenydate HCl (MPH) were simulated and obtained from literature (formulation Q and Metadate CD, respectively). Monte Carlo simulations were performed to simulate the test drug concentration profiles and BE assessment was carried out utilizing the mean (method 1) and individual concentration time curves (method 2). For formulation Q, adding pAUC₀₋[subscript Tmax] to current BE criteria reduced the possibility of passing BE from approximately 98% to 85%, with a true negative rate of 5%. The earlier the time points used to determine for pAUC before Tmax, the lower the chance of passing BE for the test product. The possibility of passing BE varied and depended on the coefficient of variations (CV) of T[subscript lag], K[subscript a] and K[subscript e] and that considerable variability in the parameters affected the earlier segments of the drug concentration profile curves more. Similar drug concentration time profiles between the test and reference products is recommended to ensure bioequivalence occurs with a reasonable subject sample size. A similar scenario was seen when Metadate CD was used as the reference product. PK M&S can help provide appropriate additional metrics to assure the BE test is a better tool ensuring therapeutic equivalence for MR products with little negative impact to generic manufacturers. Predictions can also be made about the required sample size and the chances of passing BE with any addition to the conventional three criteria for the test product. PK M&S was also used to predict drug concentrations of levofloxacin in tissue. Levofloxacin has been widely used in clinical practice as an effective broad-spectrum antimicrobial, however tendonitis and tendon rupture have been reported with increasing use of this agent. Here, these incidents will be assessed by investigating pharmacokinetic behavior of the compound to see if they are related to drug's tissue disposition. The PK model for levofloxacin was established. Mean concentration time profiles of single or multiple dosing of 500 mg levofloxacin following oral and IV infusion administration were simulated. Monte Carlo simulation was used to simulate the drug concentration time profiles in plasma (compartment 1) and tissue (compartment 2) after seven dosing regimens while varying the drug's elimination and distribution rates to see the effect of changing those rates have on the drug accumulation in tissue. Monte Carlo Simulation shows that low elimination rates affect the drug concentration in plasma and tissue significantly with the level in plasma rising up to 35 μg/mL at day 7. A normal elimination rate together with escalation of distribution rates from plasma to tissue could increase the tissue concentration after 7 doses to 9.5 µg/mL, a value that is more than twice that of normal. PK M&S can be used as an effective tool to evaluate drug concentration in different compartments (plasma and tissues, for example). The unexpectedly high concentration values in some cases may explain, at least in part, the reason of tendinopathy occurs in the clinical setting. / Graduation date: 2012 / Access restricted to the OSU Community at author's request from June 7, 2012 - June 7, 2014