Preparation and in vitro/in vivo evaluation of azilsartan osmotic pump tablets based on the preformulation investigation.

The objective of this study was to design and evaluate azilsartan osmotic pump tablets. Preformulation properties of azilsartan were investigated for formulation design. Azilsartan osmotic pump tablets were prepared by incorporation of drug in the core and subsequent coating with cellulose acetate and polyethylene glycol 4000 as semi-permeable membrane, then drilled an orifice at the center of one side. The influence of different cores, compositions of semipermeable membrane and orifice diameter on azilsartan release were evaluated. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f2). The optimal formulation achieved to deliver azilsartan at an approximate zero-order up to 14 h. The pharmacokinetic study was performed in beagle dogs. The azilsartan osmotic pump tablets exhibited less fluctuation in blood concentration and higher bioavailability compared to immediate-release tablets. Moreover, there was a good correlation between the in vitro dissolution and in vivo absorption of the tablets. In summary, azilsartan osmotic pump tablets presented controlled release in vitro, high bioavailability in vivo and a good in vitro-in vivo correlation.

Preparation and in vitro evaluation of pregabalin controlled porosity osmotic pump tablets / 中国药科大学学报

@#In this study, pregabalin controlled porosity osmotic pump tablets which are taken once a day were prepared. Single-factor tests were carried out to investigate the influence of excipients and manufacturing process. The formulation was optimized through orthogonal experiment on three levels of three significant factors including the amount of sodium citrate, and polyethylene glycol 400 and coating weight gain. On the basis of the results of the single-factor tests and the orthogonal experiment, optimal formulation and manufacturing process were obtained. The final tablet formulation contained pregabalin(82. 5 mg), microcrystalline cellulose(40%), sodium citrate(27. 5%), magnesium stearate(0. 5%)and 5% povidone K30 solution as the tablet binder; the coating formulation consisted of cellulose acetrate and 60% of polyethylene glycol 400 as a porogen; the coating weight gain was 3%. In vitro drug release kinetic study suggested that the drug release from controlled porosity osmotic pump tablets was mainly driven by osmotic pressure, which was barely affected by the pH of the release medium. The drug release behavior of the tablets within 12 hours complied with zero-order release rule and the linear correlation coefficient was 0. 991 6. The obtained porosity osmotic pump tablets could effectively slow the drug release rate, reduce concentration fluctuation and improve the safety and convenience for the patients, hence with broad prospects.

Formula Optimization of Captopril Timing Osmotic Pump Tablets / 中国药房

OBJECTIVE:To optimize the formula of Captopril timing osmotic pump tablets. METHODS:Using accumulative release rate (Q) as index, single factor test was used to investigate the effects of blocking layer coating weight gain, semipermeable membrane coating weight gain,the type of polyepoxide (PEO),the amount of PEO (3 × 105) and HPMC in drug bearing layer,the amount of PEO (7 × 106) and NaCl in booster layer on drug release of Captopril timing osmotic pump tablets. Based on single factor investigation,using comprehensive score of release behavior(L)as index,the amount of PEO(3×105)and HPMC in drug bearing layer,the amount of PEO(7×106)and NaCl in booster layer as factors,L9(43)orthogonal test was used to optimize the formula of tablet core validation test was conducted. RESULTS:The optimal formula of tablet core included PEO(3× 105)71 mg and HPMC 15 mg in drug bearing layer,PEO(7×106)61 mg and NaCl 18 mg in booster layer,coating weight gain 7％ and semipermeable membrane coating weight gain 10％ in blocking layer. The osmotic pump tablet prepared by optimized formula released after 4 h;in vitro drug release regression equation was Q=5.118t-21.441(R2=0.9956),which was in line with zero-order release characteristics. CONCLUSIONS:The optimal formula is stable,feasible and controllable in quality,and can provide reference for further development of Captopril timing osmotic pump tablets.

Preparation and Formula Optimization of Diphenidol Hydrochloride Push-pull Osmotic Pump Tablets / 中国药师

Objective: To prepare diphenidol hydrochloride push-pull osmotic pump tablets and in-vestigate the influence of differ-ent factors on in-vitro drug release. Methods: The cumulative release of different formulas was detected. Using the cumulative release and similarity factor f2as the evaluation criterion, single factor experiment was applied to screen the core formula and coating process. Results: The drug release behavior was affected by the content of PEO in the drug containing layer, the content of NaCl and the weight gain of the coating layer. After the formula was optimized, the NaCl content in the drug containing layer was 10mg, the PEO-N10 con-tent was 15mg. In the push layer, the content of PEO-WSR303 was 60 mg, that of NaCl was 20 mg. The optimized coating liquid for-mula contained 1. 25 g·L-1PEG4000 and the coating weight gain was 7% of the core. The optimized formula fitted a zero-order equa-tion within 2-12h with the drug release equation of Q=6. 308t-2. 5037(r=0. 995 8). Conclusion: The preparation technology of di-phenidol hydrochloride push-pull osmotic pump tablets is stable, and the in-vitro drug release fits zero-order model.

Development and Evaluation of High Bioavailable Sustained-Release Nimodipine Tablets Prepared with Monolithic Osmotic Pump Technology.

BACKGROUND: Frequent administration caused by short half-life and low bioavailability due to poor solubility and low dissolution rate limit the further application of poorly water-soluble nimodipine, although several new indications have been developed. To overcome these shortcomings, sophisticated technologies had to be used since the dose of nimodipine was not too low and the addition of solubilizers could not resolve the problem of poor release. OBJECTIVE: The purpose of this study was to obtain sustained and complete release of nimodipine with a simple and easily industrialized technology. METHODS: The expandable monolithic osmotic pump tablets containing nimodipine combined with poloxamer 188 and carboxymethylcellulose sodium were prepared. The factors affecting drug release including the amount of solubilizing agent, expanding agent, retarding agent in core tablet and porogenic agent in semipermeable film were optimized. The release behavior was investigated both in vitro and in beagle dogs. RESULTS: It was proved that the anticipant release of nimodipine could be realized in vitro. The sustained and complete release of nimodipine was also realized in beagles because the mean residence time of nimodipine from the osmotic pump system was longer and Cmax was lower than those from the sustained-release tablets in market while there was no difference in AUC(0-t) of the monolithic osmotic pump tablets and the sustained release tablets in market. CONCLUSION: It was reasonable to believe that the sustained and complete release of poorly watersoluble nimodipine could be realized by using simple expandable monolithic osmotic pump technology combined with surfactant.

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet.

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5 mg VNP composed of Maisine™ 35-1, Transcutol® HP, and Cremophor® EL was adsorbed on the solid carrier Aeroperl®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel®, HPMC-K4M, PVP-K30, and Lubripharm®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 32*21 full factorial design was adopted. The independent variables were: type of coating material (X1), concentration of coating solution (X2), and number of drills (X3). The dependent variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

Study on Preparation of Methylphenidate Hydrochloride Bipolar Controlled Release Osmotic Pump Tablets / 中国药师

Objective: To study the preparation method and process optimization of methylphenidate hydrochloride biphasic controlled-release osmotic pump tablets.Methods: Based on the preparation technology of double-layer osmotic pump slow-release tablets and combined with the principle of biphasic drug release behavior, the two-release preparation with two different release phases was prepared.Through the single-factor investigation of the drug-containing layer and the booster layer, the amount of the auxiliary materials was determined.The optimum compression method and the optimum coating parameters were obtained by studying the process parameters of tabletting and coating.Results: The prepared methylphenidate biphasic controlled-release osmotic pump tablets had two different release phases.The methylphenidate hydrochloride controlled-release osmotic pump tablets produced by the optimal formulat were good in appearance and reproducibility of drug content.In vitro release curves showed that the drug was released rapidly in the intial 0-2 hour time interval and was in line with zero-order release in 2-10 hour with good reproducibility.Conclusion: The preparation method is scientific, simple and complete, and can be used for preparation of methylphenidate hydrochloride biphasic controlled-release osmotic pump tablets.

Study on Preparation Technology and in vitro Drug Release Behavior of Baicalin Monolithic Osmotic Pump Tablets / 中国药房

OBJECTIVE:To prepare Baicalin monolithic osmotic pump tablets and investigate its in vitro drug release behavior. METHODS:Using accumulative release rate as evaluation index,baicalin solid dispersion was prepared to improve solubility,sin-gle factor test and orthogonal test were used to optimize preparation technology(the amount of penetrating agent and pore-forming agent,weight gaining of coating film) of monolithic osmotic pump tablets using baicalin solid dispersion as intermediate. Release rate and mechanism of samples prepared by optimized technology were investigated in 3 kinds of release medium (water,0.1 mol/L HCl,simulated gastric fluid). RESULTS:The optimal preparation technology was that penetrating agent sodium chloride was 30 mg;pore-forming agent polyethylene glycol 400 was 20% amount of excipient cellulose acetate;weight gaining of coating film was 2%. RSD of 12 h accumulative release rate was 1.06%(n=3)for 3 batches of Baicalin monolithic osmotic pump tablets pre-pared by optimized technology. 12 h accumulative release rate of them in 3 kinds of medium were similar to each other,being all more than 80%. Release equation was in line with zero-order drug release model (r=0.9985). CONCLUSIONS:Prepared Ba-icalin monolithic osmotic pump tablets after optimization can release drug at controlled rate.

Preparation and in vitro Release Study of Diphenidol Hydrochloride Double-layer Osmotic Pump Tablets / 中国药房

OBJECTIVE:To prepare Diphenidol hydrochloride double-layer osmotic pump tablets,and study its in vitro release characteristics. METHODS:Double-layer compressing technique and film coating technology were conducted to prepare Diphenidol hydrochloride double-layer osmotic pump tablets. The in vitro releases of it,Difenidol hydrochloride tablets in market,self-made Difenidol hydrochloride single-layer osmotic pump tablets were compared. RESULTS:The formulation was as follow as diphenidol hydrochloride 75 mg,sodium chloride 10 mg,low-molecular-weight polyoxyethylene 15 mg and right amounts of 5% PVP K30 ethanol solution. Booster layer was high-molecular-weight polyoxyethylene 60 mg,sodium chloride 20 mg,PVP K306 mg,right amounts of magnesium stearate. 12 h cumulative release(Q)of prepared double-layer osmotic pump tablets reached 80%,and the release was in line with zero-order kinetic equation. Q15 min of Difenidol hydrochloride tablets had reached 90%;Q12 h of Difenidol hy-drochloride single-layer osmotic pump tablets was only 51.14%. CONCLUSIONS:The prepared Difenidol hydrochloride dou-ble-layer osmotic pump tablets have sustained release effect,with more complete drug release within 12 h than single-layer one.

Preparation of micronized nimodipine push-pull osmotic pump tablets / 药学实践杂志

Objective To prepare micronized nimodipine push-pull osmotic pump (PPOP) controlled release tablets . Methods The nimodipine as a model drug ,micronization technique was applied to the PPOP method .Designed and prepared the controlled release of the nimodipine tablet for 12 hours in vitro .The factor f2 was used to evaluate the similarities of differ-ent dissolution profiles ,and the optimal formulation was performed .Results The micronized nimodipine PPOP controlled re-lease tablets were successfully prepared with excellent zero-order release characteristics .The PPOP tablet′s release behavior was close to the zero-order release equation (r= 0 .998 4) .Conclusions The controlled-release formulation was prepared suc-cessfully .Micronized technique combined with the PPOP method significantly increased the release of the nimodipine tablet , the poorly soluble drug ,in vitro .

Preparation and characterization of silymarin synchronized-release microporous osmotic pump tablets.

The pharmacological activity of herbal medicine is an overall action of each component in accordance with their original proportion. An efficient, sustained, and controlled-release drug delivery system of herbal medicine should ensure the synchronized drug release of each active component during the entire release procedure. In this study, silymarin (SM), a poorly soluble herbal medicine, was selected as a model drug to develop a synchronized-release drug delivery system: an SM microporous osmotic pump (MPOP) tablet. The SM was conjugated with phospholipid (SM phytosome complex, SM-PC) to improve the solubility, and the difference in the apparent octanol-water partition coefficient between the two components was significantly reduced. The dissolution rate of SM-PC was significantly higher than SM active pharmaceutical ingredients and was the same as that of the commercial SM capsule. The SM-PC was used to generate the MPOP tablet. SM was mixed with poly(ethylene) oxide and sodium chloride (an osmotic agent) to form the MPOP core, followed by coating with cellulose acetate and poly(ethylene) oxide to generate the SM MPOP. The results demonstrated that SM MPOP could synchronically and sustainably release the five active components within 12 hours (the similar coefficient f 2 between two components was >65), and the average cumulative release rate was 85%. Fitting of the drug-release curve showed a zero-order release profile for SM MPOP. Our study showed that the phytosome complex technique combined with the MPOP system will achieve synchronized release of the various active components of herbal medicine and have potential applications in developing sustained release preparations in herbal medicine.

Establishment of Drug Release Determination Method for Methylphenidate Hydrochloride Bipolar Con-trolled Release Osmotic Pump Tablets / 中国药师

Objective:To establish the drug release determination conditions and method for methylphenidate hydrochloride bipolar controlled release osmotic pump tablets. Methods: The drug release of the tablets was determined by HPLC using a Diamonsil C18 (250 mm × 4. 6 mm, 5 μm) column with acetonitrile-KH2 PO4 (0. 02 mol·L-1 ,and pH was adjusted to 3. 0 by 1% H3 PO4 solution) (30∶ 70) as the mobile phase at a flow rate of 1 ml·min-1 , the column temperature was 35 ℃ and the injection volume was 20 μl. The effects of release medium, release apparatus and rotation speed on the release of methylphenidate hydrochloride bipolar controlled release osmotic pump tablets were studied as well. Results:The established drug release determination method had a good linear rela-tionship within the range of 1. 0-24. 0 μg·ml-1(r=0. 999 5), and the average recovery was 100. 5%(RSD=1. 58%, n = 6). Un-der the conditions of 900 ml pH 3. 0 phosphate buffer solution as the release medium and the rotation speed of 50 r·min-1 , the drug was quickly released in 0-2h, and then the release behavior was complied with a zero-level model in vitro in 2-10h with the release e-quation of Q=5. 505t+44. 221(r=0. 994 5). Conclusion:The method is simple, accurate and reliable, and suitable for the quality control of methylphenidate hydrochloride bipolar controlled release osmotic pump tablets.

Controlled release of metformin hydrochloride and repaglinide from sandwiched osmotic pump tablet.

The marketed compound tablet of metformin hydrochloride (MH) and repaglinide (RG) exhibits perfect multidrug therapeutic effect of type 2 diabetes. However, due to the short half life of the drugs, the tablet has to be administered 2 to 3 times a day, causing inconvenience to patient and fluctuations of plasma concentration. Here, a sandwiched osmotic pump tablet was developed to deliver the two drugs simultaneously at zero-order rate, in which MH and RG were loaded in different layers separated by a push layer. The osmotic pump tablet was prepared by a combination of three tableting procedure and film coating method. The factors including type and amount of propellant, osmotic active agents, amount of porogenic agent, coating weight, orifice diameter were optimized. The pharmacokinetic study was performed in beagle dogs, and the drug concentration in plasma samples was assayed by HPLC-MS/MS method. Simultaneous, controlled release of MH and RG in the first 12 and 8h was achieved from the optimized formulation. A significantly decreased Cmax, prolonged Tmax and satisfactory bioavailability of the osmotic pump tablet were obtained, and a good in vivo-in vitro correlation of the two drugs was also established. In summary, the sandwiched osmotic pump tablet released the MH and RG simultaneously at zero-order rate, and exhibited significant sustained release effect in vivo and good in vivo-in vitro correlation. The designed controlled release system for MH and RG proposed a promising replacement for the marked compound product in the therapy of type 2 diabetes.

Preparation of osmotic pump tablets ginsenoside Rg3 of solid dispersion and its release characteristic in vitro / 中草药

Objective: To compare the differences on release behaviors between the mono-layer and two-layer osmotic pump tablets of ginsenoside Rg3 solid dispersion and to find out the advantages and disadvantages of each preparation. Methods: The mono-layer and two-layer osmotic pump tablets of ginsenoside Rg3 solid dispersion were prepared and the prescription optimization was examined by comparing the in vitro release behaviors such as type and amount of the osmotic active substances, amount of suspending agent, amount of porogen in the coating solution, and thickness of the coating. Results: Mono-layer and two-layer osmotic pump tablets were well accorded with the zero-order equation. Fitting with the zero-order release model, the coefficients of the mono-layer and two-layer osmotic pump tablets were r1=0.998 1 and r2=0.990 6, respectively. Conclusion: Two-layer Rg3 osmotic pump tablets could release more completely than mono-layer osmotic pump tablets, but have more complex preparation process.

Formulation optimization of Kyllinga brevifolia total flavonols solid dispersion controlled porosity osmotic pump tablets / 中草药

Objective: To prepare Kyllinga brevifolia total flavonols (KBTF) solid dispersion controlled porosity osmotic pump tablets, and investigate the effects of core tablets and coating on its in vitro drug release behavior, so as to optimize the formulation. Methods: Using KBTF solid dispersion prepared by solvent method as drug core to increase the dissolution of KBTF in vitro, the optimal forrmulation of KBTF solid dispersion controlled porosity osmotic pump tablets was selected via the single factor investigation and orthogonal design. Results: The optimal formula was as follows: osmotic promoter was sodium chloride 100 mg, content of PEG 400 was 150%, content of DBP was 20%, and rate of weight growth of coating membrane was 2%. Conclusion: KBTF solid dispersion controlled porosity osmotic pump tablets with optimal forrmulation can stably release drugs in 12 h and the accumulative drug release rate was more than 90%, whilst its in vitro drug release behavior was up to the character of zero-order drug release.

Feasibility of optimizing trimetazidine dihydrochloride release from controlled porosity osmotic pump tablets of directly compressed cores.

The aim of this study was to develop and optimize Trimetazidine dihydrochloride (TM) controlled porosity osmotic pump (CPOP) tablets of directly compressed cores. A 2(3) full factorial design was used to study the influence of three factors namely: PEG400 (10% and 25% based on coating polymer weight), coating level (10% and 20% of tablet core weight) and hole diameter (0 "no hole" and 1 mm). Other variables such as tablet cores, coating mixture of ethylcellulose (4%) and dibutylphthalate (2%) in 95% ethanol and pan coating conditions were kept constant. The responses studied (Yi ) were cumulative percentage released after 2 h (Q%2h), 6 h (Q%6h), 12 h (Q%12h) and regression coefficient of release data fitted to zero order equation (RSQzero), for Y 1, Y 2, Y 3, and Y 4, respectively. Polynomial equations were used to study the influence of different factors on each response individually. Response surface methodology and multiple response optimization were used to search for an optimized formula. Response variables for the optimized formula were restricted to 10% â©½ Y 1 â©½ 20%, 40% â©½ Y 2 â©½ 60%, 80% â©½ Y 3 â©½ 100%, and Y 4 > 0.9. The statistical analysis of the results revealed that PEG400 had positive effects on Q%2h, Q%6h and Q%12h, hole diameter had positive effects on all responses and coating level had positive effect on Q%6h, Q%12h and negative effect on RSQzero. Full three factor interaction (3FI) equations were used for representation of all responses except Q%2h which was represented by reduced (3FI) equation. Upon exploring the experimental space, no formula in the tested range could satisfy the required constraints. Thus, direct compression of TM cores was not suitable for formation of CPOP tablets. Preliminary trials of CPOP tablets with wet granulated cores were promising with an intact membrane for 12 h and high RSQzero. Further improvement of these formulations to optimize TM release will be done in further studies.

Preparation of microporous osmotic pump tablets of marine / 中国药科大学学报

Aim: To develop marine microporous osmotic pump tablets and to investigate drug release in vitro of the optimized formulation and the release mechanism.Methods: Wet granulation and film-coating were used to develop marine micro-osmotic pump tablets.In vitro release studies were applied to evaluate the impacts of various factors on the release of the formulation.Central-composite design was exploited to aid the optimization of the formulation,and the mechanism of in vitro release was characterized.Results: There existed fairly good reproducibility in the preparation of marine micro-osmotic pump tablets.It was found that no change in the release rate of the tablets were elicited by the pH of the release media,the rotating speed selected,the hardness of the tablet core,and the amount of the plasticizer incorporated into the coating formulation.It was proved that the release of marine micro-osmotic pump tablets was closely related to the magnitudes of NaCl amount in the tablet core and the pore former in the coating formulation as well as the coating level.In addition,there existed 12-hr zero-order kinetics in the in vitro release study of the tablets.Moreover,it was shown that the osmotic pressure-controlled delivery is greatly responsi-ble for the release of the developed tablets.Conclusion: The prepared marine microporons osmotic pump tablets are expected to be a new sustained-release medication.

Optimization of the Formulation of Bezafibrate Osmotic Pump Tablets by Central Composite Design-response Surface Methodology / 中国药房

OBJECTIVE: To prepare bezafibrate osmotic pump tablets(BOPT) and optimize its formulation by central composite design-response surface methodology(CCDRSM).METHODS: The amount of polyoxyethylene(PEO) N80 which used as an adjuvant of Bezafibrate osmotic pump tablets(A),the amount of Na2CO3(B),and the coating weight increase(C) were used as 3 factors for investigation,and the cumulative release amount at 1 h and 6 h respectively,and the linear correlation coefficient(r) of the cumulative release amount versus time were taken as indexes.The formulation of BOPT was optimized by CCDRSM and the optimized formulation was verified.RESULTS: The optimized formulation obtained was as follows: A 40 mg,B 20 mg,and C 29 mg.The tablets prepared in optimized formulation demonstrated good release behavior,with the absolute value of deviation of each index being less than 5%.CONCLUSION: The CCDRSM can be applied to optimize the formulation of BOPT and the established model is of satisfactory predictive value.

Core formulation optimization of Osmotically Controlled Release Tablets of colchicine / 中成药

AIM: To investigate the optimum core formulation and drug release profile of colchicine osmotic pump tablets. METHODS: The key influencing factors and optimum core formulation were studied based on the cumulative drug release rate at different timepoints and homogenous factor(f_2) in combination with the orthoganal design. RESULTS: The drug release profile in vitro was influenced by components of the core tablet,including(amount) of osmogent,solubilizer and adherent.The optimum in vitro drug release profile obeyed the zero-order release model within 1～10 h(r=0.990 2),and drug released at 12h reached up to 85%. CONCLUSION: The colchicine osmotic-pump tablets are attainable by constant speed delivery.

Preparation and dissolution test in vitro of matrine controlled porosity osmotic pump tablet / 中成药

AIM: To study prescription and process of matrine controlled porosity osmotic pump tablet (matrine CPOPT) and to inspect release property in vitro. METHODS: The orthogonal experiment was designed to screen prescription and process which were definited with the evaluation of release of tablet. RESULTS: The optimization of prescription was definited: osmotic agent consisted of mannitol and lactose with a ratio of 1 ∶ 1(g/g); weight of osmotic agent was 2 fold increase of matrine; the cellulose acetate in coating liquid accounted for 15% (g/g) of PEG 400; The release behavior of matrine CPOPT was coincident with zero-order rate equation well and characteristic of controlled-release. CONCLUSION: Matrine CPOPT has good controlled-release in vitro effect and experiments for further in vivo test are available.