Formulation,Bioavailability, and Pharmacokinetics of Sustained-Release Potassium Chloride Tablets

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 ± 32% from hydroxypropyl methylcellulose, 95 ± 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 ± 29% from commercially available sustained-release tablets, and 97 ± 13% from enteric-coated tablets. There was no significant difference (P > 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.     

Development and in Vitro-in Vivo Evaluation of a Multiparticulate Sustained Release Formulation of Diltiazem

Purpose. To develop and evaluate the in vitro/in vivo performance of diltiazem sustained release pellets that were prepared by the Wurster column process. Methods. Pellets containing diltiazem were prepared by spraying a slurry of micronized diltiazem hydrochloride, pharmaceutical glaze and alcohol onto an appropriate mesh fraction of nonpareil seeds using the Wurster column. A two-step drug layering process was used to increase drug loading from 60% to 75%. The oven-dried diltiazem basic pellets were coated with eth-ylcellulose/dibutyl sebacate coating solution to yield diltiazem sustained release pellets. An open, randomized Latin square, three-way crossover clinical study was used to evaluate the in vivo performance of the coated product. Results. Altering the mesh fraction of the starting nonpareil seeds for this layering process was found to affect the release characteristics of drug from the pellets. An oven-drying step was required to stabilize the diltiazem basic pellets. The thicker the drug loading layer the longer the oven drying is needed to stabilize the pellets. The diltiazem sustained release pellets produced by these methods displayed sustained release dissolution profiles both in vitro and in vivo. Diltiazem basic pellets coated with a 0.6% ethylcellulose/dibutyl sebacate coating showed a different rate of absorption (lower C _max and higherT _max) and the same extent of absorption as compared to Cardizem^® tablets. Conclusions. Clinical data confirmed that this formulation approach is an effective means to produce a diltiazem sustained release product.     

The Controlled Release of Prednisolone Using Alginate Gel

In a release study of alginate gel beads, swelling and erosion of the beads were observed at pH 6.8, whereas no swelling occurred at pH 1.2. The amount of released prednisolone (PL) was greater at pH 6.8 than at pH 1.2. The lower the ratio of mannuronic acid block to guluronic acid block in alginate, the slower the release of PL. An increase in loaded PL in the beads resulted in a slower release of PL. The decrease in bead size caused a rapid release of PL. The addition of sodium alginate propylene glycol ester elevated the extent of PL release. The plasma profile of PL showed sustained-release behavior after the oral administration of the beads to beagles. Furthermore, the correlation between in vitro release and in vivo absorption of PL for various alginate gel beads was evaluated using deconvolution and convolution methods. The in vivo absorption of PL was correlated with the PL release at pH 1.2, and it differed from that at pH 6.8. The release of PL from alginate gel beads in vivo appeared to occur under conditions that cause little swelling.     

盐酸特拉唑嗪渗透泵控释片的制备及其释药特性的研究

目的制备盐酸特拉唑嗪口服渗透泵控释片,考察其释药影响因素及释药机理。方法通过考察渗透泵片体外释药速率,并根据不同时间累积释放度考察药物的释放情况来研究口服渗透泵制剂的释药特性。结果制备得到了盐酸特拉唑嗪口服渗透泵控释片,其体外释药速率较平稳。结论盐酸特拉唑嗪口服渗透泵控释片遵从以渗透压差为释药动力的释药模式,在15h内呈现良好的零级释药特征。     

In Vitro Controlled Release of Alfuzosin Hydrochloride Using HPMC-Based Matrix Tablets and Its Comparison with Marketed Product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r² value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

In Vitro/in Vivo Correlation for 14C-Methylated Lysozyme Release from Poly(Ether-Ester) Microspheres

PURPOSE: The purpose of this study was to obtain an in vitro/in vivo correlation for the sustained release of a protein from poly(ethylene glycol) terephthalate (PEGT)/poly(butylene terephthalate) (PBT) microspheres. METHODS: Radiolabeled lysozyme was encapsulated in PEGT/PBT microspheres via a water-in-oil-in-water emulsion. Three microsphere formulations varying in copolymer composition were administered subcutaneously to rats. The blood plasma was analyzed for radioactivity content representing released lysozyme at various time points post-dose. The in vitro release was studied in phosphate-buffered saline. RESULTS: The encapsulation efficiency, calculated from the radioactivity in the outer water phase of the emulsion, varied from 60-87%. Depending on the PEG segment length and wt% PEGT, the lysozyme was released completely in vitro within 14 to 28 days without initial burst. 14C-methylated lysozyme could be detected in the plasma over the same time courses. The in vitro/in vivo correlation coefficients obtained from point-to-point analysis were greater than 0.96 for all microsphere formulations. In addition, less then 10% of administered radioactivity remained at dose site at 28 days for the microsphere formulations, indicating no notable retention of the protein at the injection site. CONCLUSION: The in vitro release in phosphate-buffered saline and the in vivo release in rats showed an excellent congruence independent of the release rate of 14C-methylated lysozyme from PEGT/PBT microspheres.     

盐酸青藤碱渗透泵控释片的体内外相关性研究

制备了盐酸青藤碱渗透泵控释片.以正清风痛宁缓释片为参比制剂,考察其体外释放度和Beagle犬体内吸收情况.自制控释片与参比制剂的主要药动学系数:AUCo-1(11.01±3.2)和(13.06±3.5)μg·ml-1·h,t1/2(27.8±2.6)和(8.6±1.9)h,cmax(790.8±126.3)和(1334.5±150.5)ng/ml.结果表明,自制控释片的体外释放符合零级动力学方程.采用HPLC法测定血药浓度,照Wagner-Nelson法计算药物的体内吸收分数,对响应时间的体外累积释放率线性回归,所得方程的相关系数为0.98.     

A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.     

Formulation Influence on Conjunctival Penetration of Four Beta Blockers in the Pigmented Rabbit: A Comparison with Corneal Penetration

The objective of this study was to compare the influence of pH, tonicity, benzalkonium chloride, and EDTA on the conjunctival and corneal penetration of four beta blockers—atenolol, timolol, levobunolol, and betaxolol. Drug penetration was evaluated using the isolated pigmented rabbit conjunctiva and cornea in the modified Ussing chamber. The conjunctiva was more permeable than the cornea to all four beta blockers. Formulation changes caused larger changes in corneal than in conjunctival drug penetration, especially for the hydrophilic beta blockers, atenolol and timolol. Raising the solution pH to 8.4 caused the largest increase in corneal penetration for all drugs except atenolol. This increase was greater than that obtained by removing the corneal epithelium. The same formulation also increased conjunctival drug penetration, although to a lesser extent. In the case of timolol, the formulation changes evaluated brought about similar changes in its ocular and systemic absorption with good in vitro–in vivo correlations. The above findings indicate that in making formulation changes to maximize corneal drug penetration, it is necessary to evaluate possible changes in conjunctival drug penetration, hence systemic absorption. Moreover, because the conjunctiva plays an active role in the noncorneal route of ocular drug absorption, the relative contribution of the noncorneal to the corneal routes to ocular drug absorption may also be altered by formulation changes.     

Release and Absorption Characteristics of Novel Theophylline Sustained-Release Formulations: In Vitro-in Vivo Correlation

Five new experimental sustained-release (SR) formulations of theophylline, T-l, T-l-A, T-2, T-2-A, and T-2-E, in a matrix tablet form with a protein were developed. The in vitro release of theophylline from these novel experimental formulations and two commercial (Theotrim and Theo-Dur) SR formulations, was studied for 2 hr immersed in simulated gastric fluid TS, followed by an additional 10 hr immersed in simulated intestinal fluid TS. Like Theotrim and Theo-Dur, theophylline release profiles from all the novel experimental formulations were smooth, controlled, and unaffected by changes in the pH and the proteolytic enzyme content of the incubation media. Pharmacokinetic evaluation of T-l, T-l-A, T-2-A, Theotrim, and Theo-Dur was carried out in five dogs and six healthy human volunteers under fasting conditions, using immediate-release aminophylline tablets as controls. Pharmacokinetic analysis by the Wagner–Nelson procedure revealed sustained-release absorption characteristics for all the formulations with the exception of the immediate release aminophylline tablet. For each of the formulations tested, the regression analysis results of the percentage of theophylline absorbed in dogs or humans against the mean percentage released in vitro, at the corresponding times, indicated a high correlation. These data imply that the in vivo release profiles under fasting conditions in the gastrointestinal tract of dogs and humans may be similar to those in the in vitro studies.     

Controlled Release of Lidocaine from Injectable Gels and Efficacy in Rat Sciatic Nerve Block

Purpose. Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine. Methods. Release of lidocaine from 2% lidocaine-HC1 containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37°C. Commercial metylcellulose gel (MC_com) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested. Results. The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivoresults. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels. Conclusions. Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.     

The Development of USP Dissolution and Drug Release Standards

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.     

An in Vitro/in Vivo Correlation for the Disintegration and Onset of Drug Release from Enteric-Coated Pellets

An empirical mass-transfer model for enteric-coating dissolution that uses in vitro dissolution data to characterize the pH-dependent solubility properties of the polymer film and a mass-transfer coefficient determined from in vivo dissolution or disintegration studies is developed. Once the in vivo mass- transfer coefficient has been evaluated, it can be used in conjunction with in vitro dissolution data from other formulations to predict the in vivo time to disintegration and onset of drug release. Results of in vitro dissolution experiments using the USP basket dissolution apparatus and in vivo disintegration experiments using gamma scintigraphy with four enteric-coated pellet formulations are presented. The good agreement among the in vivo mass-transfer coefficients that were determined supports the validity of the model.     

Formulation and In vitro Evaluation of Sustained Release Dosage Form with Taste Masking of Metformin Hydrochloride

An attempt was made to sustain the release of metformin HCl as well as to mask the bitter taste by complexation technique using strong cation-exchange resins, indion 244 and indion 264. The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized using XRPD and IR. Using resinate sustained release tablets were formulated using hydoxypropylmethylcellulose K100M.The tablets were evaluated for hardness, thickness, friability, drug content, weight variation and in vitro drug release. Tablets thus formulated (Batch B-6) provided sustained release of drug over a period of 10 h with first order kinetics. The release of metformin HCl from resinate controls the diffusion of drug molecules through the polymeric material into aqueous medium. Results showed that metformin HCl was successfully taste masked and formulated into a sustained dosage form as an alternative to the conventional tablet.     

Modification of the Dialysis Membrane Method for Drug Release from Suppositories

Pharmaceutical Research -     

A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

The importance of hydrodynamics in the development of in vitro–in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.     

Correlation of in Vitro Release Rate and in Vivo Absorption Characteristics of Four Chlorpheniramine Maleate Extended-Release Formulations

An in vitro/in vivo correlation was established for four formulations of chlorpheniramine maleate (histamine, H₁-blocker) extended-release tablets exhibiting different in vitro release rate characteristics. In vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2, paddle stirrer at 50 rpm in 1000 ml of distilled water at 37.0 ± 0.5°C. Inspection of the individual and mean release rate data indicated that the in vitro release rate of chlorpheniramine maleate was consistent with the intended design of the four extended-release formulations. The in vivo bioavailability and pharmacokinetics of these formulations were evaluated in 24 healthy subjects under fasting conditions. Wagner Nelson analyses of the in vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a statistically significant correlation (r ² > 0.98, P < 0.001) for each formulation. Qualitative rank-order correlations were observed among all combinations of in vitro and in vivo parameters. These data support a Level A correlation between the in vitro release rate profiles and the in vivo absorption for chlorpheniramine maleate determined under fasting conditions.     

非洛地平-美托洛尔缓释片处方优化及体外释放一致性评价

目的 优化非洛地平-美托洛尔缓释片的处方,并评价其与市售制剂体外释放的一致性。方法 采用HPLC测定非洛地平-美托洛尔缓释片中非洛地平及美托洛尔的释放度;以体外释放度为评价指标,重点考察了固体分散体、微丸以及片芯中关键处方因素对非洛地平/美托洛尔释放行为的影响,进一步优化处方。结果 微丸组成、微丸粒径、微丸衣膜中致孔剂用量、微丸增重以及片芯中阻滞剂用量均影响药物释放;处方优化后自制的非洛地平-美托洛尔缓释片与市售制剂在0.3% SDS水溶液、含0.3% SDS的pH 4.0的柠檬酸缓冲液、含0.3% SDS的pH 6.8的磷酸盐缓冲液、含0.3% SDS的0.1 mol·L^-1 HCl中的体外释放行为一致。结论 自制非洛地平-美托洛尔缓释片与市售制剂的体外释放行为一致。     

Effect of Omeprazole on Diazepam Disposition in the Rat: in Vitro and in Vivo Studies

Purpose. The inhibitory effects of omeprazole on diazepam metabolism in vitro and in vivo are compared in the rat. Methods. 3-hydroxylation and N-demethylation of diazepam was investigated in the presence of a range of omeprazole concentrations (2-500µM) in hepatic microsomes and hepatocytes. Zero order infusions together with matched bolus doses of omeprazole were used to achieve a range of steady state plasma concentrations (10-50mg/ L) and to study the diazepam-omeprazole interaction in vivo. Results. The 3-hydroxlation pathway was more prone to inhibition (K_Is 108 ± 30 and 28 ± 11 µM in microsomes and hepatocytes, respectively) than the demethylation pathway (K_Is of 226 ± 76 and 59 ± 27 µM in microsomes and hepatocytes, respectively). In both in vitro systems, the mechanism of inhibition was competitive with Km/K_I ratios larger than 1 for the 3HDZ pathway and smaller than 1 for the NDZ pathway. There was an omeprazole concentration dependent decrease in diazepam clearance in vivo which could be modelled using a simple inhibition equation with a K_I of 57µM (19.8mg/L). In contrast there was no statistically significant change in the steady state volume of distribution for diazepam in the presence of omeprazole. Conclusions. The in vivo K_I for the omeprazole: diazepam inhibition interaction shows closer agreement with the K_I values obtained in hepatocytes than with those observed in microsomes.     

In Vitro/In Vivo Comparison of Drug Release and Polymer Erosion from Biodegradable P(FAD-SA) Polyanhydrides—A Noninvasive Approach by the Combined Use of Electron Paramagnetic Resonance Spectroscopy and Nuclear Magnetic Resonance Imaging

Purpose. The purpose of this study was to compare drug release and polymer erosion from biodegradable P(FAD-SA) polyanhydrides in vitro and in vivoin real time and with minimal disturbance of the investigated system. Methods. P(FAD-SA) 20:80 and P(FAD-SA) 50:50 polymer tablets were loaded with the spin probe 3-carboxy-2,2,5,5-tetramethyl-pyrrollidine-1-oxyl (PCA) and implanted subcutaneously in the neck of rats or placed in 0.1 M phosphate buffer. 1.1 GHz EPR spectroscopy experiments and 7T MRI studies (Tl and T2 weighted) were performed. Results. A front of water penetration was visible by MRI in vitro in the case of P(FAD-SA) 20:80, but not for P(FAD-SA) 50:50. For both polymers, the thickness of the tablets decreased with time and a insoluble, easy deformable residue remained. Important processes such as edema, deformation of the implant, encapsulation and bioresorption were observable by MRIin vivo. P(FAD-SA) 50:50 was almost entirely absorbed by day 44, whereas an encapsulated residue was found for P(FAD-SA) 20:80 after 65 days. The EPR studies gave direct evidence of a water penetration induced changes of the microenvironment inside the tablet. EPR signals were still detectable in P(FAD-SA) 20:80 implants after 65 days, while the nitroxide was released in vitro within 16 days. Conclusions. Important parameters and processes such as edema, deformation of the tablet, micro viscosity inside the tablet and encapsulation can be monitored in real time by the combined use of the noninvasive techniques MRI and EPR leading to better understanding of the differences between the in vitroandin vivo situation.