Disposition of 14C-Quinelorane in Dogs Following Oral or Intravenous Dosing and Transdermal Patch Application

Abstract

A transdermal patch was developed to circumvent the emesis associated with the oral and intravenous administration of a dopamine agonist, quinelorane, to dogs.

Approximate steady-state plasma concentrations were achieved following the daily application of a transdermal patch for 7 days. Each dog received between 0.1 and 0.2 mg/kg per day from the transdermal patch.

At steady-state conditions, dogs received either a single oral dose of ¹⁴C-quinelorane at 0.1 mg/kg, a bolus intravenous dose of 0.03 mg/kg or had a transdermal patch containing the radioactive free base, ¹⁴C-quinelorane, applied to their abdomens for 24 hours; the approximate dose was 0.18 mg/kg.

The plasma pharmacokinetics were measured by liquid scintillation counting and ELISA.

The systemic bioavailability of quinelorane, as measured by the ELISA, was 30%, indicative of first-pass metabolism.

The radioactive urinary metabolite profile was similar for all three routes of administration. Principal entities in the urine were quinelorane, the N-despropyl- and the hydroxy-lactam- metabolites, accounting for 29, 25 and 3% of the dose, respectively. The major route of excretion of radioactivity was via. the urine, irrespective of the route by which the drug was administered.     

Polymeric Pseudolatices Dispersion Bearing Isosorbide Dinitrate for Transdermal Application

A pseudolatex based system for transdermal delivery (PL-ISDN-D) of isosorbide dinitrate (ISDN) was developed for its prolonged and controlled systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL-100 and polyvinylpyrrolidone were used in the preparation of pseudolatices polymeric dispersions. These preparations were evaluated for in-vitro release and permeation of the drug across human cadavar skin. The designed systems exhibited linear relationship between drug release (Q) Vs 0.80 function of time (t^0.80).

The product exhibiting required skin permeation (500 mcg/h/ 100 mg) calculated to achieve an effective plasma concentration was selected for the in-vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of conventional oral dose of isosorbide dinitrate.

The study revealed that designed pseudolatex transdermal drug delivery system of isosorbide dinitrate could be used successfully with improved performance.     

In Vitro and in vivo Availability of Spironolactone from Various Oral Preparations

The dissolution rates in vitro and the bioavailability in humans were determined for 6 preparations containing 25 mg spironolactone and 5 preparations containing 100 mg spironolactone. Linear relationships were obtained by pairwise correlation of in vitro parameters with in vivo parameters. The following parameters were used.

In vitro parameters of dissolution:

1. The area under the dissolution-time-curve up to 1 h

2. The fraction of active ingredient dissolved within 20 min.

3. The slope of the dissolution-time-curve at 50 % dissolution

4. The dissolution rate constant

5. The time up to 50 % dissolution of the substance

6. The maximum slope of the dissolution-time-curve

In vivo parameters of bioavailability:

1. The time of maximum plasmaconcentration

2. The area under the plasmaconcentration-time-curve up to 1 h and 2 h after application

3. The quantities of active ingredient excreted in the urine up to 2 h after application

The highest correlation coefficient was found between the areas beneath the dissolution-time-curve and the plasmaconcentration-time-curve up to 1 h each.

No significant correlations were found between the within 1 h dissolved substance and maximum plasma-concentration, the area under the plasmaconcentration-time-curve up to 4 h and 24 h and quantities of active ingredient excreted in the urine up to 4 h after application.     

Dissolution Characteristics of Pharmaceutical Equivalents

The in-vitro release of diltiazem from pharmaceutical equivalents of sustained release tablets, commercially available in Italy, was studied.

The in-vitro release profiles were determined by means of different methods and apparatus. Paddle, basket, Poole, Diffutest and Stricker methods were compared.

The absorption rates in artificial gastric and enteric juices by means of lipid barriers were calculated.

Some preparations showed a diffusion mechanism, some a first-order release.

The differences among the dissolution profiles of the formulations were enhanced with the Strieker method.     

Development and Evaluation of Transdermal Salbutamol Delivering Systems

ABSTRACT

The transdermal drug delivery systems based on polymeric pseudolatex and matrix diffusion controlled systems for salbutamol were prepared and compared for in vitro skin permeation profile and in vivo performances. Poly (isobutylene) was used as release controlling polymer in both the systems. In vitro skin permeation was studied using the human cadavar skin in franz diffusion cell. Permeation rate constants for matrix diffusion controlled system and pseudolatices were 10.625 and 13.750 mcg/hr/cm² respectively. The prepared transdermal systems were tested on human volunteers having chronic reversible airways obstruction and compared with oral treatments (Asthaline). The in vivo drug plasma profiles following transdermal and oral treatments reveal that although peak plasma level by oral administration was higher in comparison with the transdermal treatments, troughs and peaks were discernible at dosing times. In the case of transdermal treatments, constant drug plasma and FEV₁ levels were recorded indicating controlled and systemic delivery of drug spaced over 30 hours. Among the prepared transdermal drug delivery systems, pseudolatices demonstrated better drug plasma profile, maintained at relatively higher level and flatter in appearance. The relative performance of the systems was noted to reflect in AUC and FEV₁.     

Medicament Release from Suppository Bases: II. Naproxen Physicochemical Characteristics and Bioavailability in Rabbits

Suppositories containing 25mg naproxen were prepared by the fusion method with tehobroma oil, PEG 1000, and witepsol 11-15. The liguefaction point and the time for complete liquefaction at temperatures from 37°C to 47°C were determined. By utilizing the SBT (Erwka) apparatus it was determined that the witepsol 11-15 formed supposltories which were more brittle.

The In vitro release rates were determined by using the USP method and by a modified one with dialyzing cellophane tubing. Samples withdrawn at definite time interval for up to 6 hours, and were analyzed by the spectrofluorometric method. The in vivo drug release was studied in rabbits. Ten blood samples were collected over a 24 hour period following administration of a 25mg dose of each suppository and of oral suspension. Plasma samples were assayed by spectrofluorometric method. A student “t” test was conducted on all date from the four different formulations and indicated significant difference between theobroma oil and oral suspension.

Significant correlation was obtained between the in vivo absorption and in vitro release when the suppository was placed In a dialyzing cellophane membrane.     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Preparation and Evaluation of Sustained-Release Solid Dispersions of Drugs with Eudragit Polymers

Coevaporates of paracetamol and rifampicin with Eudragit polymers of different natures (anionic, cationic, and zwitterionic) were prepared. Determination of dissolution rate of these coevaporates in dissolution media simulating those of the gastrointestinal tract (GIT) revealed that the release rate of paracetamol is retarded from all the coevaporates studied. In this respect, Eudragit L100-SS shows the highest sustainment of drug release, while Eudragit E100 shows the lowest. Conversely, the release of rifampicin from its coevaporates with the anionic Eudragit S100 polymer is more retarded than the corresponding coevaporate with the zwitterionic Eudragit RL100 or from coevaporates with equal mixtures of the two polymers.

Increasing the polymer weight fraction in rifampicin coevaporates with Eudragit S100 up to 0.5 resulted in a corresponding decrease in the dissolution rate. However, beyond this weight fraction, the polymer effect on the dissolution rate of the drug becomes minimized. The results confirmed that the process of dissolution of the two drugs from their coevaporates is a diffusion-controlled release process.

The biological performance of paracetamol coevaporates was monitored in rabbits; paracetamol level in plasma was found to follow first-order kinetics. for all the investigated paracetamol coevaporates, the peak plasma level was less than 50 μg/ml compared to a value of 60, μg/ml for the drug per se. The coevaporates of the drug with Eudragit L100-55 showed slowest rates of absorption and elimination as well as greatest half-peak and half-life times. Biological peformance of rifampicin coevaporates was assessed in human subjects receiving a single oral dose equivalent to 300 mg of the drug. The results depicted sustainment of drug release as a function of polymer weight fraction. A strict correlation was shown to exist between the total amount of drug excreted during 24 hr post dosing of the coevaporates and its in vitro dissolution rate.

The results depicted that paracetamol can be formulated in the form of a coevaporate with Eudragit L100-55 to prepare a more safe sustained-release formulation with minimal side effects, and also revealed the advantages of administration of rifampicin in the form of a coevaporate with Eudragit S100 (4:1) at a single oral dose equivalent to 600 mg of drug.     

Habit Modifications of Nitrofurantion Crystallized from Formic Acid Mixtures

The crystal size and the length to width ratio of Nitrofurantoin, an anti-bacterial urinary tract drug, can be controlled using an appropriate mixture of solvents and suitable crystallization conditions.

Some solvents will form undesirable complexes with the drug (INF) while with others no crystal structure modification or complexation was detected (HCO₂H).

The length (y) to width (x) ratio of the Nitrofurantoin varies from 2.5 to 1.5 when crystallized from pure formic acid or in a mixture with water or ethanol.

The y/x values correspond to the solvent interactions and super saturation (S).

The crystal growth regularity is ascribed to the solvent power and thus when more regular crystals will precipitate bioavailability and solubilization of the drug will increase. Best results were obtained when mixture of formic acid-ethanol solution was used as crystallization media yielding large tabular crystals.     

Stability Indicating Hplc Method for Ribavirin and its Pharmaceutical Dosage Forms

The present work describes a specific, stability indicating HPLC method for determination of Ribavirin (1) and its pharmaceutical dosage forms.

Ribavirin was chromatographed on a microbondapak C18 column utilizing a simple mixture of 0.01M dibasic potassium phosphate and methanol (95: 5). The detection was done at 207 nm.

The available literature was scanned to locate the various methods(2,3) available along with the one reported in USP XXII.

A comparative study was made of the proposed method and USP method and the advantages over the USP method have been discussed.

The low value of Relative standard deviation and recovery of the drug in the range of 99.1% to 101.5% indicates a good precision and non-interference of the method.     

Dependence of Compression Phase on Elasticity of the Material

It is shown that the Pmax value obtained during the tabletting process is statistically independent of machine motor velocity

To explain this phenomenon, an analogic model composed of a spring and two or three Maxwell bodies grouped in parallel was used to represent the behaviour of powders during compaction. It was observed that during the compression phase, the recorded force may be represented by the response given by the set of springs alone

The shock absorbers intervene just before and after the Pmax, when the upper punch velocity is very low or nil

It was possible to obtain these results after determining the law representing elasticity in relation to the deformation applied to the powders

The consequences of these phenomena are discussed     

Freeze-Dried Preparations of Ketoprofen and Heptakis- (2, 6-O-Dimethyl) -β-Cyclodextrin

ABSTRACT

The purpose of this study was to examine the inclusion formation in freeze-dried preparations of ketoprofen and heptakis-(2,6-0-dimethyl)-β-cyclodextrin. The products obtained were amorphous mixtures of the two components. X-ray diffractography, differential scanning calorimetry, ¹³C-CPMAS-NMR spectroscopy and thermofractography did not give any proof of an inclusion of ketoprofen in the cyclodextrin cavity.     

Methods for the Determination of the Carbon Dioxide Evolved from Effervescent Systems

Different methods for determining the carbon dioxide evolved from effervescent systems are described. In addition, a comparison between some of them is carried out when a stoechiometric mixture of L-tartaric acid and sodium bicarbonate reacts.

The methods compared are: gravimetric, volumetric and gasometric.

The gravimetric methods can be direct or indirect. The direct ones are based on taking in the carbon dioxide by a sorbent substance. The increase of weight after the absorption represents the CO₂ evolved. In the indirect gravimetric methods the amount of carbon dioxide is determined by substraction of the weight of the sample after and before the effervescent reaction.

The volumetric methods are based on an acid-base titration. In the method used, the carbon dioxide released reacts with barium hydroxide. The excess of barium hydroxide is titrated with oxalic acid. It is possible to calculate then the carbon dioxide produced in the reaction from the volume of oxalic acid used.

In the gasometric methods the volume of gas is directly determined by the displacement of a solution when the gas is released.

The gasometric method seems to be the most efficient among the studied ones.     

Multivariate Analysis of Variance of Dissolution Data in the Development of Oral Sustained Release Formulations

A multivariate analysis of variance applied to polinomial interpretation of growth curves in used for the interpretation of dissolution curves of four experimental, sustained release, wax type theophylline tablets.

The factors under study were glyceril palmitic stearate, carboxypol imethylene contents and compression force. The tablets were formulated according an experimental design based on 4 × 4 Hadamard matrix. The USP type I apparatus for dissolution test and CHI 0.1 N plus O.1%. polysorbate 80 as dissolution medium was used.

The statistical interpretation of results showed: first, that dissolution rates were almost constant for the four formulations during 8 h; second, the main difference between formulation dissolution rates can be inputed to fat excipient content and in much lesser extent to carboxipolymethylene content; third, the theopylline release rate was unaffected by compression force.     

Use of Statistical Experimental Design in Laboratory Scale Formulation Optimisation and Progression to Plant Scale

The objective of these studies was to optimise the formulation of a dry powder blend to be filled into hard gelatin capsules and progress the product to plant production. The blend was to contain two active compounds (500mg active A and lOmg active B). Preliminary work had limited the independent formulation variables to levels of filling aid, glidant and lubricant. The effects and interactions of the independent variables were assessed using an augmented factorial experimental design demanding the examination of 31 formulations at small scale (less than 3kg). Critical dependent variables identified were blend homogeneity and flow, capsule weight variation and active dissolution rate.

The study plan was to assess blend flow and active dissolution using formulations manufactured at laboratory scale (less than 3kg), select the optimum formulation, confirm the data and determine blend homogeneity at development scale (upto 30kg) and progress to pilot plant production (250kg).

Statistical software was employed to fit response surfaces to optimisation data and generate 3-dimensional plots which were used to assess interactions of excipients and effects on dependent variables. From the 3-dimensional plots it was possible to estimate maxima and minima on the response surfaces enabling selection of optimum combinations of excipients. Using this technique a formulation has been devised which has now been successfully manufactured at development and plant scale. Results obtained at laboratory, development and plant scale were compared and found to be not significantly different.

A comparison of estimated resource expenditure indicated that a conventional approach would have required approximately 350 man hours less than the statistical approach. However, using a conventional approach there is a higher risk of production batch failure, rework or troubleshooting exercises resulting in estimated equivalent losses of 350, 250, and 100 man hours respectively.

The statistical approach is proposed as an aid to formulation optimisation and has several advantages in providing an improved data base, ensuring product robustness, giving higher quality assurance and facilitating troubleshooting. In addition, careful experimental design permits accurate resource estimation and allocation with known gains.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Hydroxypropylmethylcellulose sustained release technology

The use of polymers in controlling the release of drugs has become important in the formulation of pharmaceuticals. Watersoluble polymers such as polyethylene glycol and polyvinylpyrrolidone may be used to increase the dissolution rates of poorly soluble drugs (Ford)¹ and slowly soluble, biodegradable polymers such as polylactic acid may be used for controlled release implants (Rak et a1.²), Hydrogels provide the basis for implantation, transdermal and oral-controlled release systems. Hydroxypropylmethylcellulose (HPMC) are cellulose ethers which may be used as the basic for hydrophilic matrices for controlled release oral delivery.

In tablet matrix systems the tablet is in the form of compressed compact containing an active ingredient, lubricant, excipient, filler or binder. The matrix may be tabletted from wet-massed granules or by direct compression.

This review article examines a previously published series of work and concentrates on the following aspects of the subject; the relationship between release rate and quantity of polymers, such consideration allow a certain predicability in release rates to be made. Also the effect of drug particle size, tablet shape and the presence of additional diluents in the formula are examined.     

Physicochemical Study of the Adsorption of Oxprenolol Hydrochloride by Montmorillonite

The interaction between oxprenolol hydrochloride and montmorillonite was studied by adsorption isotherms, x-ray diffraction and i.r. spectroscopy.

The adsorption isotherm fits Langmuir's equation and the maximum amount of oxprenolol adsorbed by the clay is 70 mEq/100 g of clay.

The results of x-ray diffraction studies and i.r. spectroscopy reveal that the oxprenolol molecule is adsorbed into the interlayer space of the clay and that the mechanism of adsorption is cation exchange.