Stability,in-Vitro and in-Vivo Release Studies from Metronidazole Ointments

Abstract

The influence of ointment formulation on the stability, the in-vitro release and the in-vivo absorption through the skin of rabbits was investigated. The choice of the selected ointments has no influence on the drug stability with the exception of an acidified emulsion base. A good correlation between in-vitro release and in-vivo absorption was found revealing that metronidazole was quickly released and effectively absorbed from a polyethylene glycol base.     

Mucosal Delivery of Progestational Steroids from a Controlled Release Device: In-Vitro/In-Vivo Relationships

The mucosal delivery of progestational steroids from a model controlled release device was studied using female New Zealand White rabbits as the animal model. A controlled release device was developed which was suitable for nasal, rectal and vaginal application. The in-vitro permeation and in-vivo absorption of progesterone from the model controlled release device was investigated through the nasal, rectal and vaginal mucosa. The influence of penetrant hydrophilicity on the in-vitro permeation and in-vivo absorption from the controlled release device was also investigated using the mono-hydroxy, di-hydroxy and tri-hydroxy derivatives of progesterone. The results indicate that the nasal route demonstrates a significantly higher rate of in-vitro permeation and extent of in-vivo absorption than the rectal and vaginal mucosa. The in-vitro permeation rates and steady-state plasma concentrations achieved from the device tend to decrease with increasing penetrant hydrophilicity. A linear in-vitro/in-vivo correlation was obtained for all the mucosa studied. The slope of the relationship between the in-vitro and in-vivo data was similar for the rectal and vaginal mucosa. The results of this investigation agree with the results of a previous investigation with a solution formulation, and suggest that the hydrodynamic and/or membrane barrier properties of the nasal mucosa may from that of the rectal and vaginal mucosa.     

Mucosal Delivery of Progestational Steroids from a Controlled Release Device: In-Vitro/In-Vivo Relationships

Abstract

The mucosal delivery of progestational steroids from a model controlled release device was studied using female New Zealand White rabbits as the animal model. A controlled release device was developed which was suitable for nasal, rectal and vaginal application. The in-vitro permeation and in-vivo absorption of progesterone from the model controlled release device was investigated through the nasal, rectal and vaginal mucosa. The influence of penetrant hydrophilicity on the in-vitro permeation and in-vivo absorption from the controlled release device was also investigated using the mono-hydroxy, di-hydroxy and tri-hydroxy derivatives of progesterone. The results indicate that the nasal route demonstrates a significantly higher rate of in-vitro permeation and extent of in-vivo absorption than the rectal and vaginal mucosa. The in-vitro permeation rates and steady-state plasma concentrations achieved from the device tend to decrease with increasing penetrant hydrophilicity. A linear in-vitro/in-vivo correlation was obtained for all the mucosa studied. The slope of the relationship between the in-vitro and in-vivo data was similar for the rectal and vaginal mucosa. The results of this investigation agree with the results of a previous investigation with a solution formulation, and suggest that the hydrodynamic and/or membrane barrier properties of the nasal mucosa may from that of the rectal and vaginal mucosa.     

Medicament Release from Ointment Bases: IV. Piroxicam: In-vitro Release and In-Vivo Absorption in Rabbits

Abstract

Several ointment bases containing 1% piroxicam were studied to determine the in-vitro release of the drug. The general rank order of the drug release was found to be: Modified hydrophilic ointment > hydrophilic ointment USP > water washable base > modified U.C.H. base > hydrophilic petrolatum > U.C.H. base. Furthermore, it was found that additives such as urea, ethanol and DMSO at 1%, 3% and 5% concentration levels had no significant effect in enhancing the release of piroxicam from the modified hydrophilic ointment base. The in-vitro release data were assessed by various kinetic principles in order to determine the relevant parameters such as diffusion, permeability and partition coefficients. The in-vitro absorption of 1% and 3% piroxicam in hydrophilic base was determined in rabbits. It was found that the addition of 5% DMSO increases the drug absorption. The statistical evaluation of the in-vivo release data was done using one-way ANOVA.     

Pharmacokinetic and In-Vitro Characteristics of Sustained Release Verapamil Products

The in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan (V) and Isoptin SR (ISR), were compared. The effect of food on V was also examined in a separate study with conventional Isoptin (I) as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for ISR and 8 hours for V. The extended in-vitro profile of V versus ISR was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for V and ISR respectively. In a second pharmacokinetic study the rate and extent of absorption of verapamil from V was shown to be unaffected by food.     

Pharmacokinetic and In-Vitro Characteristics of Sustained Release Verapamil Products

Abstract

The in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan (V) and Isoptin SR (ISR), were compared. The effect of food on V was also examined in a separate study with conventional Isoptin (I) as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for ISR and 8 hours for V. The extended in-vitro profile of V versus ISR was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for V and ISR respectively. In a second pharmacokinetic study the rate and extent of absorption of verapamil from V was shown to be unaffected by food.     

Diadermatic Dose Forms Of Testosterone: In-Vitro Release Studies and in-Vivo Absorption In A Human Male

Abstract

The study was undertaken to evaluate the in-vitro release of testosterone from various topical bases and to screen formulations with the optimum drug release for in-vivo evaluations in a human male. Several diadermatic bases containing 2% testosterone were prepared and studied for the in-vitro release of drug through the cellulose membrane using the diffusion methods. Also, additive ingredients such as, ethanol, polyethylene glycol-400, and dimethylsulfoxide (DMSO) at various concentration levels were included in these formulations to study their effects on the release rate of the drug. The general rank order of testosterone release from these bases was: water-washable base > hydrophilic base > University of California Hospital Base > gel base > cream base > water-soluble base > emulsion base. Except for the water-washable base containing 15% polyethylene glycol-400, all additives had little or no effect on the drug release. The formulations with the best in-vitro drug release were selected and evaluated for in-vivo drug release in a single male volunteer. Each formulation equal to 50mg of testosterone was applied on the forearm, and following each application, 24 hour urine samples were collected and analyzed for the Urinary free testosterone and its principal metabolites, i.e. androsterone and etiocholanolone. A 50mg of oral testosterone in a plain gelatin capsule was used as the control to compare the bioavailability profiles. The ratio of urinary-free testosterone to its main metabolites was found to be (1:1) from one of the topical formulations evaluated compared to (1:20) obtained in the case of oral dose of testosterone used as the control. This suggests that more drug was able to escape the pre-systemic inactivation and resulted in the higher level of free testosterone in the body.     

In-Vitrodn-Vivo Correlation of Drug Liberation with an Extended Release Peroral Dosage form for Iloprost in Man

Abstract

Iloprost is a chemically stable prostacyclin analogue for which therapeutic efficacy was demonstrated after i.v. infusion treatment in several vascular diseases. In order to facilitate drug therapy and to enlarge therapeutic usability an peroral dosage form for non-hospitalized patients was developed on the basis of an extended release (ER) pellet formulation mimicking therapeutic plasma levels as obtained after i.v. infusion in man. Modified drug liberation was pH-independent and showed an in-vitro release of 75 to 95 5% of dose over 3 h at pH 7.4 using the basket method. In 12 PAOD-patients the pharmacokinetic profile of the ER-formulation in capsules (SH K 529 I/M) was characterized after repeated administration of 150 μg iloprost as compared to a standard i.v. infusion treatment with iloprost (Ilomedin®). Peroral treatment resulted in highly reproducible plasma level profiles in the therapeutic range (> 50 pg/ml) for approx. 6 h, i.e. a similar time period as obtained after i.v. infusion. Half-value duration was approx. 4 h. AUC accounted for 0.8 ± 0.2 ng·h/ml as compared to 1.0 ± 0.2 ng·h/ml (i.v.), bioavailability was 19 ± 5%. A level A correlation (1:1 correlation) of in-vitro liberation and in-vivo absorption could be set up based upon individual plasma level data by means of the Wagner-Nelson method. Linear correlations with a slope of approx. I were obtained when plotting dose fraction released in-vitro vs. dose fraction absorbed in-vivo. Half-lives of liberation in-vitro and in-vivo were similar. A lag-time for the onset of in-vivo absorption was observed caused by disintegration of the dosage form and liquid mediated formation of ER diffusion membrane on the pellets.

The present ER-dosage form of iloprost provides long-lasting plasma levels of iloprost in the therapeutic range and thus might be a clinically effective equivalent of i.v. infusion, which can easily be used by ambulant patients. The intraindividual reproducibility and the correlation of in-vitro and in-vivo performance of the modified release preparation are prerequisites for efficacy, safety and patient compliance.     

Studies on the Delivery Mechanisms of Theophylline from a Sustained Release Tablet

The in-vitro and in-vivo release of theophylline from an oral sustained release tablet (Theograd^R) was studied.

The in-vitro release profiles were determined by means of the rotating basket method, the paddle method and the modified disintegration method, described in the USP XX as apparatus 1, 2 and 3 respectively. Besides a stationary basket-rotating paddle method was used.

It was demonstrated that in the stationary basket-rotating paddle apparatus and in the paddle apparatus at low rotational speeds of the paddle, mild agitation conditions were created. Under these conditions the release of theophylline from the sustained release tablet appeared to be matrix controlled. The leached matrix was found to be structurally very weak. For a matrix type of sustained release tablet this is probably beneficial as it would be less likely to cause accumulation and gastro-intestinal obstruction. In contrast the conditions of agitation in the rotating basket apparatus and in the disintegration apparatus were found to be rather severe. This was partly due to mechanical abrasion of the dosage form caused by the gauze of the basket and the basket-rack respectively, and partly the result of high solvent agitation, especially in the disintegration apparatus. Under these conditions it appeared that the empty matrix of the sustained release tablet eroded during the release process. This was confirmed by the results of studies under non-dissolving circumstances of the drug which showed that in this case only the leached matrix of the sustained release dosage form eroded and not that part of the dosage form from which the drug had not yet been dissolved. The in-vivo absorption appears to relate to the in-vitro release. When the Theograd tablet was taken on an empty stomach, it appeared that the absorption rate could succesfully be simulated by means of the stationary basket-rotating paddle method and the paddle method, both at low rotational speeds of the paddle. It was very likely that in this case the in-vivo release from the sustained release tablet was matrix controlled too. Under these conditions the bioavailability was found to be 65% compared with an oral solution of the drug. In contrast, when the Theograd tablet was taken after a meal, a relative bioavailability of 90% was observed. It was made plausible, that the greatly enhanced bioavailability, observed on postprandial administration of the tablet, was due to partial erosion of the leached matrix. This erosion was caused by the food induced increased motility of the gastro-intestinal tract. Based on the results of this study it is recommended to take Theograd^R tablets after a meal.     

Mucoadhesive delivery systems. II. Formulation and in-vitro/in-vivo evaluation of buccal mucoadhesive tablets containing water-soluble drugs

From the previous work (Part I), mucoadhesive formulae containing 5% CP/65% HPMC/30% lactose and 2% PC/68% HPMC/30% mannitol as well as formulae based on sodium carboxymethyl cellulose (SCMC) were selected. Medicated tablets were prepared using diltiazem hydrochloride (DZ) and metclopramide hydrochloride (MP) in two different doses (30 and 60 mg). The effect of drug and dose on the mucoadhesive properties and in-vitro drug release was evaluated. All formulae produced extended drug release (over 8 to 12 h). Polyacrylic acid based matrices (PAA) showed Fickian's diffusion release pattern for both drugs. SCMC ensured zero-order release for DZ, which deviated to anomalous behavior in case of MP. Doubling the dose significantly reduced the bioadhesion strength (p<0.05) with a slight improvement in drug release rate. The formulation of bilayer tablets containing drug-free layer and medicated layer enhanced the drug release without affecting the bioadhesive performance. The bilayer tablet formulated with 2% PC/68% HPMC/30% mannitol (PC2) was selected for studying the in-vivo metoclopramide release in four healthy volunteers. The tablet ensured controlled drug release for 12 h, in addition, good correlation (r=0.9398) was observed between in-vitro and in-vivo data. The effect of ageing on selected formulae containing DZ and MP, respectively, was studied. Storage at 40 degrees C and 75% relative humidity for 6 months didn't influence the mucoadhesive performance, however, an enhanced released rate was observed.     

Medicament Release From Ointment Bases: V. Naproxen In-Vitro Release and In-Vivo Percutaneous Absorption In Rabbits

Abstract

The in- vitro release of Naproxen from various ointment bases, including a water-washable base with the drug in the water phase (I) and the drug in the oil phase (II), a hydrophilic base with the drug in the water phase (III), and the drug in the oil phase (IV), and an anhydrous ointment (V), a gel (VI) and a modified University of California (U.C.H.) base (VII) were studied. In addition, the effects of various additives (urea, ethanol, dimethyl sulfoxide and polyethylene glycol-400) on the release of Naproxen from formulations (I) and (II) were determined. Low concentrations of urea and ethanol in the formulations increased the release of the drug from both these bases, however, higher concentrations adversely affected the release of the drug. While dimethyl sulfoxide (DMSO) had no significant effect on the drug release, the inclusion of polyethylene glycol-400 in both bases decreased the release of Naproxen.

The percutaneous absorption of Naproxen from the waterwashable base (drug in the oil phase) and hydrophilic base (drug in the oil phase) were studied by applying the ointments on rabbit's skin. It was observed that the bioavailability of Naproxen from the hydrophilic base was slightly greater than that from the water-washable base, and that DMSO had no effect in enhancing the in-vivo release of Naproxen from the ointments evaluated. Using the in-vivo data, the absorption and elimination rate constants, the half-life and AUC were calculated.     

Medicament Release From Ointment Bases: V. Naproxen In-Vitro Release and In-Vivo Percutaneous Absorption In Rabbits

The in- vitro release of Naproxen from various ointment bases, including a water-washable base with the drug in the water phase (I) and the drug in the oil phase (II), a hydrophilic base with the drug in the water phase (III), and the drug in the oil phase (IV), and an anhydrous ointment (V), a gel (VI) and a modified University of California (U .C .H.) base (VII) were studied. In addition, the effects of various additives (urea, ethanol, dimethyl sulfoxide and polyethylene glycol-400) on the release of Naproxen from formulations (I) and (II) were determined. Low concentrations of urea and ethanol in the formulations increased the release of the drug from both these bases, however, higher concentrations adversely affected the release of the drug. While dimethyl sulfoxide (DMSO) had no significant effect on the drug release, the inclusion of polyethylene glycol-400 in both bases decreased the release of Naproxen.

The percutaneous absorption of Naproxen from the waterwashable base (drug in the oil phase) and hydrophilic base (drug in the oil phase) were studied by applying the ointments on rabbit's skin. It was observed that the bioavailability of Naproxen from the hydrophilic base was slightly greater than that from the water-washable base, and that DMSO had no effect in enhancing the in-vivo release of Naproxen from the ointments evaluated. Using the in-vivo data, the absorption and elimination rate constants, the half-life and AUC were calculated.     

The effects of PH, Ionic concentration and ionic species of dissolution media on the release rates of quinidine gluconate sustained release dosage forms

The dissolution profiles of some extended release quinidine gluconate products were shown to be dependent on several dissolution medium variables. It was shown that, for a quinidine gluconate wax matrix tablet, the dissolution rate has an unexpected inverse relationship to the solubility as a function of pH. The dissolution rate is also affected by the concentration of chloride ion present in the dissolution medium apparently due to the inhibition of disintegration. It was found that the nature of the anion (inorganic vs. organic) of the dissolution buffer plays a significant role in the release of the drug. Salts of inorganic acids used as part of the buffer system lower the rate of release of quinidine gluconate from wax matrix tablets through an inhibition of disintegration. On the other hand, buffer salts of organic acids do not have any appreciable effect on the disintegration or dissolution of these tablets. Since the concentration of chloride ion in both gastric and intestinal juices is approximately 0.1M, this suggests that the use of a dissolution medium containing chloride ion represents the more appropriate approach when an in-vivo/in-vitro correlation is desired. For all the quinidine gluconate controlled release formulations studied, mechanisms of release are of at least two different types. This makes the selection of a single dissolution medium for in-vivo/in-vitro correlations either improbable or impossible.     

Piroxicam Release from Dermatological Base: In-Vitro Studies using Cellulose Membrane and Hairless Mouse Skin

Abstract

Piroxicam is one of the most potent non-steroidal, anti-inflammatory agents which also exhibits antipyretic activity. Piroxicam is well absorbed following the oral administration, however, its use has been associated with a number of gastro-intestinal disorders including bleeding and ulceration. To overcome these side effects, this study was undertaken to develop diadermatic dosage form using various polymeric gel and ointment bases containing 1% piroxicam were prepared to study the in-vitro release of the drug. Also, a series of additive ingredients, such as, alcohol USP, polyethylene glycol-400 and dimethyl sulfoxide (DMSO) were incorporated in these formulations at various concentration levels to evaluate their effects on drug release. The general rank order for the in-vitro drug release from all the bases evaluated was: gel base > hydrophillic base > emulsion base. In general, additives had little or no effect in enhancing the drug release from these bases. The in-vitro release data were treated with various kinetic principles to assess the relevant parameters, such as, diffusion coefficient, permeability coefficient, partition coefficient, zero order and first order rate constants. Among the formulations evaluated, the gel base containing (DMSO) gave the best in-vitro drug release both through the cellulose membrane and the hairless mouse skin.     

In-Vitro Release Studies of Chlorpheniramine Maleate from Topical Bases Using Cellulose Membrane and Hairless Mouse Skin

Abstract

In-vitro release of chlorpheniramine maleate from various dermatological bases including a polymeric gel base, the modified hydrophilic base and the modified hydrophilic petrolatum base, was studied. The additive ingredients known to enhance the drug release from the topical bases were also evaluated at different concentration levels. These included urea, ethanol and dimethylsulfoxide (DMSO). The rank order of drug release through the cellulose membrane was observed to be: the gel base > the modified hydrophilic base > the modified hydrophilic petrolatum base. In general, the presence of the additives adversely affected the drug release except for the (DMSO) and ethanol in certain cases.

The formulations with optimum in-vitro release profiles of the drug through the cellulose membrane, were selected for further studies of the drug release using hairless mouse skin as the diffusion barrier. Here again, the gel formulation gave the best in-vitro release of the drug, and the data correlated well with the results previously obtained from the cellulose membrane.

The in-vitro data were treated with various kinetic principles to determine the relevant parameters, such as the steady state flux, the diffusion coefficient and the permeability coefficient. Using these information, the formulations were evaluated for their suitability for delivering chlorpheniramine maleate via the diadermatic dosage form.     

The Complexation of Amitriptyline and Imipramine by Sodium Polyphosphate

The complexation of organic cations with sodium polyphosphate (SPP) has received some attention in the past; those workers have focused on research which demonstrated the range of molecules which form insoluble complexes, the in-vitro dissolution of the complexes or in-vivo studies on the absorption of the complexes. This in-vitro study, with amitriptyline and imipramine, presents evidence that structurally related drugs may have substantially different affinities for the SPP. Imipramine has the higher affinity for SPP and the complexation process is unaffected by the presence of up to 0.1 M sodium chloride. The maximum stoichiometry obtained with imipramine was 1.13. It is suggested that imipramine is able to interact in a 1:1 ratio with the chain phosphates and in a 2:1 ratio with the terminal phosphates. This mechanism predicts that the net stoichiometry for SPP, with an average chain lenghth of 14, is 1.143.     

Dynamics of controlled release of heparin from swellable crosslinked starch microspheres

The microspheres of crosslinked starch have been prepared and characterized by IR spectral analysis and SEM technique. The prepared microspheres were loaded with an anticoagulant drug ‘heparin’ and the kinetics of in-vitro release of heparin was investigated spectrophotometrically at physiological pH (7.4) and body temperature (37 °C). The influence of percent loading of heparin, chemical architecture of the microspheres and pH of the release medium were examined on the release profiles of the drug. The chemical stability of heparin was tested in phosphate buffer saline (pH 7.4) and the release was also studied in various simulated biological fluids.     

Elevation of plasma levels of L-dopa in transdermal administration of L-dopa-butylester in rats

To increase delivery of L-dopa in its transdermal absorption, a new lipophilic derivative of L-dopa, L-dopa-butylester, was synthesized. An in-vitro study employing two-chamber diffusion cells, in which the excised rat abdominal skin was mounted, revealed that, in the presence of L-menthol and ethanol, L-dopa-butylester penetrated in its original form more effectively than L-dopa. L-Dopa-butylester sheets were made by immersing wiper sheets in methanol containing the compound, and then evaporating the methanol. An extraction study of the compound from the sheets revealed that its stability was maintained for at least 12 weeks. In an in-vivo cutaneous absorption study, an L-dopa-butylester sheet was attached to the shaved rat abdominal skin. A hydrogel containing L-menthol and ethanol was spread on vinyl tape, and this sheet was placed over it. In plasma, the L-dopa level rose linearly between 30 and 180 min after the cutaneous application; L-dopa-butylester was not detected. The L-dopa level was higher than that in which L-dopa was applied. These findings indicated that the lipophilic nature of L-dopa-butylester further increased its penetration through the skin, and that L-dopa-butylester that was taken up into the general circulation system was rapidly converted to L-dopa by hydrolysis in the body.     

The Complexation of Amitriptyline and Imipramine by Sodium Polyphosphate

Abstract

The complexation of organic cations with sodium polyphosphate (SPP) has received some attention in the past; those workers have focused on research which demonstrated the range of molecules which form insoluble complexes, the in-vitro dissolution of the complexes or in-vivo studies on the absorption of the complexes. This in-vitro study, with amitriptyline and imipramine, presents evidence that structurally related drugs may have substantially different affinities for the SPP. Imipramine has the higher affinity for SPP and the complexation process is unaffected by the presence of up to 0.1 M sodium chloride. The maximum stoichiometry obtained with imipramine was 1.13. It is suggested that imipramine is able to interact in a 1:1 ratio with the chain phosphates and in a 2:1 ratio with the terminal phosphates. This mechanism predicts that the net stoichiometry for SPP, with an average chain lenghth of 14, is 1.143.     

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.