Aqueous-Based Cellulose Acetate Butyrate Dispersion: Screening of Process and Formulation Variables to Obtain Verapamil HCl-Controlled Release Beads

The objectives of the present investigation were to evaluate the possibility of using a custom-designed cellulose acetate butyrate (CAB) pseudolatex dispersion on Verapamil HCl-loaded beads for sustained release of the drug. Excipient compatibility was studied by thermal analysis, X-ray diffraction, and content analysis. Inert beads (Nupareil) were loaded with verapamil HCl and subsequently coated with CAB pseudolatex dispersion. Process and formulation factors were screened by Plackett-Burman screening design in order to identify the most important factors affecting the amount of verapamil HCl released in 12 hours. X-ray diffraction pattern and content analysis showed no degradation of verapamil HCl and suggested absence of any interaction. However, thermal analysis indicated an interaction between verapamil HCl and excipient. A polynomial equation was developed to show the relationship between dependent and independent variables. The mathematical model fitted the data and explained 98.05 % of variability in the response. The difference between observed and predicated values of any given run did not exceed 6 % of maximum cumulative release at 12 hours. Plackett-Burman screening design identified coating weight gain, duration of curing, and amount of plasticizer as the most important factors determining cumulative percent released in 12 hours. Amount of Polydextrose/HPMC (Opadry II), spray rate, fluid bed coater outlet temperature, and atomizing pressure had no statistically significant (p < 0.05) influence on the response.     

Pharmacokinetics of Doxazosin Gastrointestinal Therapeutic System after Multiple Administration in Korean Healthy Volunteers

Doxazosin mesylate is a selective alpha-adrenoreceptor antagonist for the treatment of hypertension and benign prostatic hyperplasia. A simple high performance liquid chromatographic method has been developed and validated for the quantitative determination of doxazosin in plasma. A reversed phase C18 column was used for the separation of doxazosin and prazosin (internal standard) with a mobile phase composed of water ? acetonitrile ? triethylamine (68:32:0.2 v/v, pH 5.0) at a flow rate of 1.2 mL/min. The fluorescence detector was operated at 246 (excitation) and 389 nm (emission). Intra- and inter-day precision and accuracy were acceptable for all quality control samples including the lower limit of quantification of 1 ng/mL. Recovery of doxazosin from human plasma was greater than 93.4%. Doxazosin was stable in human plasma under various storage conditions. This method was used successfully for a pharmacokinetic study in plasma after oral administration of multiple 4-mg dose of doxazosin gastrointestinal therapeutic system formulation to 16 healthy volunteers. At steady state the mean area under the curve for a dosing interval and elimination half-life were calculated to be 367.0 ± 63.5 ng · hr/mL and 29.2 ± 4.5 hr, respectively. There was no difference in pharmacokinetic parameters between male and female.     

Oral Sustained Delivery of Atenolol from Floating Matrix Tablets—Formulation and In Vitro Evaluation

Floating matrix tablets of atenolol were developed to prolong gastric residence time and increase drug bioavailability. Atenolol was chosen as a model drug because it is poorly absorbed from the lower gastrointestinal tract. The tablets were prepared by direct compression technique, using polymers such as hydroxypropyl methylcellulose (HPMC K15M, K4M), guargum (GG), and sodium carboxymethylcellulose (SCMC), alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz. hardness, swelling index, floating capacity, thickness, and weight variation. Further, tablets were evaluated for in vitro release characteristics for 8 hr. The effect of effervescent on buoyancy and drug release pattern was also studied. In vitro release mechanism was evaluated by linear regression analysis. GG- and SCMC-based matrix tablets showed significantly greater swelling indices compared with other batches. The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium.     

Communications: Effects of Formulation Variables on the Pulmonary Delivery of Insulin

ABSTRACT

The effects of some formulation variables on the pulmonary absorption of insulin in presence of a bile salt, sodium glycocholate (NaGC), have been described in this report. Relationship between intratracheally administered insulin dose and pharmacodynamic response has been established. The data obtained from this study revealed that an increase in the viscosity of an aqueous formulation administered to pulmonary sacs can facilitate insulin absorption probably due to reduced mucocilliary clearance. A hypertonic formulation produced similar overall hypoglycemic effect to the isotonic solution. On the other hand, hypotonicity elicited significantly improved hypoglycemic response, probably due to membrane damage. The cumulative hypoglycemic effect of intratracheally administered insulin has been linearly correlated with the logarithmic doses.     

Study of Formulation Variables on Properties of Drug-Gellan Beads by Factorial Design

ABSTRACT

The aim of the present study was to obtain cross-linked calcium-gellan beads containing diclofenac sodium as model drug, using full 3³ factorial design. Drug quantity, pH of cross-linking solution, and speed of agitation were selected as variables for factorial design. The resultant beads were evaluated by scanning electron microscopy (SEM), percent yield, entrapment efficiency, micromeritic properties, swelling and drug release studies. The drug-loaded beads were spherical with size range of 0.85–1.8 mm. Percent yield and entrapment efficiency of various batches were in the range of 86.48–98.28% w/w and 72.52–92.74% w/w, respectively. Calcium-gellan beads containing diclofenac sodium showed pH-dependent swelling and drug release properties. Swelling and drug release were significantly higher in pH 7.4 phosphate buffer than 0.1N HCl. The swelling ratio for beads was up to 22 and 3 for phosphate buffer and 0.1N HCl, respectively. Cumulative diclofenac sodium release from calcium-gellan beads was 12–35% in 0.1N HCl within 2 h, whereas complete drug release was observed within 3–4 h in pH 7.4 phosphate buffer.     

Carbopol-Gelatin Coaceevatioh I Influence of Some Variables

Abstract

The extent and integrity of mloroenoapsulation is hypothesised to be dependent on the optimisation of sediment weight and volume. This led to the investigation of the effeota of the type of gelatin or carbopol, the ratios of the coaeervate materials, the total colloid concentrations, the starting pH of gelatin sol and the stirring rate. Investigation showed that gelatin, type A, at pH 6.8 together with oarbopol 941 gave best results. Optimum oarbopol-gelatln ratio was found to be 1/10, above whioh the sediment weight and volume decreased significantly. Increase in the total oolloid concentration results in a parallel increase in sediment weight till concentration of 1.1% w/v above whioh the increase in sediment weight was less pronounoed. A stirring rate of 300-350 r.p.m. gave an almost spherical, uniform coacervatos with averages diameter of 59 u.     

Carbopol-Gelatin Coaceevatioh I Influence of Some Variables

The extent and integrity of mloroenoapsulation is hypothesised to be dependent on the optimisation of sediment weight and volume. This led to the investigation of the effeota of the type of gelatin or carbopol, the ratios of the coaeervate materials, the total colloid concentrations, the starting pH of gelatin sol and the stirring rate. Investigation showed that gelatin, type A, at pH 6.8 together with oarbopol 941 gave best results. Optimum oarbopol-gelatln ratio was found to be 1/10, above whioh the sediment weight and volume decreased significantly. Increase in the total oolloid concentration results in a parallel increase in sediment weight till concentration of 1.1% w/v above whioh the increase in sediment weight was less pronounoed. A stirring rate of 300-350 r.p.m. gave an almost spherical, uniform coacervatos with averages diameter of 59 u.     

Micromeritic and Packing Properties of Diclofenac Pellets and Effects of Some Formulation Variables

The effects of two common diluents (microcrystalline cellulose and calcium phosphate dihydrate), two binding agents (gelatin and methacrylic polymer), and spheronization on the micromeritic (size, shape, density), flow, and packing properties of sodium diclofenac pellets were examined. The shape was assessed as the aspect ratio and was correlated to the flow rate and to the deviation of the tapped porosity from the value of 26%, which corresponds to the ideal rhombohedral packing of spheres. It was found that porosity deviation decreased greatly with spheronization, but it increased with binder addition. Porosity deviation was proportional to the aspect ratio, while flow rate decreased logarithmically with porosity deviation. Porosity deviation may be a useful index for monitoring the quality of pellets, similar to the aspect ratio, as a successful, simple, and indirect indication of sphericity and of surface roughness as well.     

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Abstract

Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.

Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leuprolide acetate and 0.05 M acetate buffer at pH 5.0. Competitive reaction of ions possibly involved in the delivery mechanism will be discussed.     

The Effects of Formulation Variables on Iontophoretic Transdermal Delivery of Leuprolide to Humans

Feasibility of applying iontophoresis to facilitate the transdermal permeation of leuprolide acetate was investigated. Because of the complexity of the factors involved in the process of iontophoresis, theoretical predictions of the combination effects from formulation variables are difficult. This study incorporated the formulation variables, drug levels and buffer concentrations, in a device prepared by Drug Delivery System, Inc., to assess the feasibility for leuprolide delivery.

Steady state serum leuprolide concentrations were achieved within 30 minutes of patch application, and were maintained for the duration of the study period. An increase in LH levels was observed for each formulation. The serum leuprolide concentrations were higher with lower drug concentration and more dilute buffer solutions. Increasing drug concentration in the patch appeared to inhibit delivery of leuprolide. A mean steady state serum concentration, 0.8 ng/ml, was achieved by a formulation composed of 10 mg/ml leuprolide acetate and 0.05 M acetate buffer at pH 5.0. Competitive reaction of ions possibly involved in the delivery mechanism will be discussed.     

Prolonged release Matrix Pellets Prepared by Melt Pelletization I. Process Variables

A melt pelletization process was investigated in an 8 litre laboratory scale high shear mixer using a formulation with paracetamol, glyceryl monostearate 40-50, and microcrystalline wax. The effects of jacket temperature, product temperature during massing, product load, massing time and impeller speed were investigated by means of factorially designed experiments. The maximum yield of pellets in the range of 500-1400μm was found to approx. 90%. For process conditions preventing deposition of moist mass, the process was found to be reproducible. Impeller speed and massing time were found to be important process variables. Remarkably low in vitro drug release rates were observed in USP-dissolution tests.     

Prolonged release Matrix Pellets Prepared by Melt Pelletization I. Process Variables

Abstract

A melt pelletization process was investigated in an 8 litre laboratory scale high shear mixer using a formulation with paracetamol, glyceryl monostearate 40–50, and microcrystalline wax. The effects of jacket temperature, product temperature during massing, product load, massing time and impeller speed were investigated by means of factorially designed experiments. The maximum yield of pellets in the range of 500–1400μm was found to approx. 90%. For process conditions preventing deposition of moist mass, the process was found to be reproducible. Impeller speed and massing time were found to be important process variables. Remarkably low in vitro drug release rates were observed in USP-dissolution tests.     

A New Transmucosal Therapeutic System: Overview of Formulation Development and in Vitro/In Vivo Clinical Performance

Abstract

A new transmucosal therapeutic system (TmTs) was developed for controlled systemic delivery of drugs, which are labile to hepatic “first-pass” metabolism, through oral mucosa. It consists of a fast-release layer, which provides a rapid release of drug for prompt rise in blood drug concentration to reach the therapeutic level, and a sustained-release layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-release layer also contains mucoadhesive composition, so TmTs can be applied on gingival mucosa for continuous transmucosal controlled administration of drugs. Using isosorbide dinitrate (ISDN), a well-known antianginal drug which is known to be subjected to extensive presystemic elimination when taken orally, the systemic bioavailability has been improved by 37 fold in beagle dogs and by almost 5 fold in humans compared to that of marketed oral sustained-release tablet and the plasma concentration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle dogs and in human volunteers. Multi-fractional absorption model has been successfully applied for pharmacokinetic analysis, which demonstrates that the rate-limiting step for the transmucosal systemic delivery is the release of ISDN from the TmTs. Clinical studies performed in the anginal patients for up to one year have demonstrated the therapeutic benefits of this TmTs in achieving a substantial reduction in the frequency of anginal attacks and prolongation in the duration of exercise time.     

Chitosan Formulations for Steroid Delivery: Effect of Formulation Variables on In Vitro Characteristics

ABSTRACT

Chitosan film formulations for steroid delivery after craniomaxillofacial surgery were formulated by using three different types of chitosan with respect to their molecular weight as low, medium and high. Film formulations were prepared by casting/solvent evaporation technique. In vitro characterization, film thickness, equilibrium swelling degree, in vitro release profiles and surface morphologies were investigated. For two different types of crosslinkings, the release of dexamethasone sodium phosphate (DSP) can be extended as the molecular weight increases. As a result, chitosan film formulations should be beneficial for steroid delivery for a certain time after craniomaxillofacial surgery.     

A New Transmucosal Therapeutic System: Overview of Formulation Development and in Vitro/in Vivo Clinical Performance

A new transmucosal therapeutic system (TmTs) was developed for controlled systemic delivery of drugs, which are labile to hepatic “first-pass” metabolism, through oral mucosa. It consists of a fast-release layer, which provides a rapid release of drug for prompt rise in blood drug concentration to reach the therapeutic level, and a sustained-release layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-release layer also contains mucoadhesive composition, so TmTs can be applied on gingival mucosa for continuous transmucosal controlled administration of drugs. Using isosorbide dinitrate (ISDN), a well-known antianginal drug which is known to be subjected to extensive presystemic elimination when taken orally, the systemic bioavailability has been improved by 37 fold in beagle dogs and by almost 5 fold in humans compared to that of marketed oral sustained-release tablet and the plasma concentration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle dogs and in human volunteers. Multi-fractional absorption model has been successfully applied for pharmacokinetic analysis, which demonstrates that the rate-limiting step for the transmucosal systemic delivery is the release of ISDN from the TmTs. Clinical studies performed in the anginal patients for up to one year have demonstrated the therapeutic benefits of this TmTs in achieving a substantial reduction in the frequency of anginal attacks and prolongation in the duration of exercise time.     

A New Transmucosal Therapeutic System: Overview of Formulation Development and in Vitro/in Vivo Clinical Performance

Abstract

A new transmucosal therapeutic system (TmTs) was developed for controlled systemic delivery of drugs, which are labile to hepatic “first-pass” metabolism, through oral mucosa. It consists of a fast-release layer, which provides a rapid release of drug for prompt rise in blood drug concentration to reach the therapeutic level, and a sustained-release layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-release layer also contains mucoadhesive composition, so TmTs can be applied on gingival mucosa for continuous transmucosal controlled administration of drugs. Using isosorbide dinitrate (ISDN), a well-known antianginal drug which is known to be subjected to extensive presystemic elimination when taken orally, the systemic bioavailability has been improved by 37 fold in beagle dogs and by almost 5 fold in humans compared to that of marketed oral sustained-release tablet and the plasma concentration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle dogs and in human volunteers. Multi-fractional absorption model has been successfully applied for pharmacokinetic analysis, which demonstrates that the rate-limiting step for the transmucosal systemic delivery is the release of ISDN from the TmTs. Clinical studies performed in the anginal patients for up to one year have demonstrated the therapeutic benefits of this TmTs in achieving a substantial reduction in the frequency of anginal attacks and prolongation in the duration of exercise time.     

A New Transmucosal Therapeutic System: Overview of Formulation Development and in Vitro/In Vivo Clinical Performance

A new transmucosal therapeutic system (TmTs) was developed for controlled systemic delivery of drugs, which are labile to hepatic “first-pass” metabolism, through oral mucosa. It consists of a fast-release layer, which provides a rapid release of drug for prompt rise in blood drug concentration to reach the therapeutic level, and a sustained-release layer, which releases the drug continuously for sustained duration to maintain the therapeutic level for up to 12 hrs. The sustained-release layer also contains mucoadhesive composition, so TmTs can be applied on gingival mucosa for continuous transmucosal controlled administration of drugs. Using isosorbide dinitrate (ISDN), a well-known antianginal drug which is known to be subjected to extensive presystemic elimination when taken orally, the systemic bioavailability has been improved by 37 fold in beagle dogs and by almost 5 fold in humans compared to that of marketed oral sustained-release tablet and the plasma concentration profile has also been prolonged to 12 hrs from less than 1 hr for marketed sublingual tablet and spray products in both beagle dogs and in human volunteers. Multi-fractional absorption model has been successfully applied for pharmacokinetic analysis, which demonstrates that the rate-limiting step for the transmucosal systemic delivery is the release of ISDN from the TmTs. Clinical studies performed in the anginal patients for up to one year have demonstrated the therapeutic benefits of this TmTs in achieving a substantial reduction in the frequency of anginal attacks and prolongation in the duration of exercise time.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

Effect of Formulation and Process Variables on the Dissolution Profile of Naproxen Sodium from Tablets

Abstract

Results of this investigation revealed some important formulation characteristics of naproxen sodium. Tablets made from the granules, prepared by wet granulation method using water, showed a significant decrease in solution as compared to those made by dry blending method. During wet granulation, heat was evolved due to the hydration of naproxen sodium resulting in the retardation of dissolution. The pseudo-polymorphism and hydration is being investigated by Bansal et. al. (1). In addition, when polyvinyl pyrolidone (PVP K-90) was used instead of PVP K-30, the dissolution was further retarted. Addition of cross carmellose sodium (Ac-Di-Sol) did not change the dissolution behavior of these tablets. When naproxen sodium was granulated with water, a decrease in dissolution rate was observed as mixing time was increased from 5 minutes to 15 minutes. The increase in hardness of the tablet from 10 Kp to 18Kp did not alter the dissolution profile of naproxen sodium. When granulation was prepared using a low shear mixer (Planetary mixer) versus a high shear mixer (T.K. Fielder), the resultant tablets exhibited similar dissolution and physical chemical properties.     

The Significance of Formulation in Drug Bioavailability I. A Study with Cimetidine Tablets

Abstract

From a variety of commercially available cimeditine products, an arbitrary sampling of seven tablet-forms, as well as, the active compound, were examined by a series of tests for the veryfication of the purity of content, the dissolution rate, disintigration time, hardness etc.

It was found that some of the products did not comply with the formulation standards, resulting in insufficient bioavailability.