In vitro characterization and release study of Ambroxol hydrochloride matrix tablets prepared by direct compression

A series of either hydrophilic or hydrophobic polymers were used to prepare controlled release Ambroxol hydrochloride (AMX) matrix tablets by direct compression. Both the compatibility and flow properties of AMX/polymer mixtures were investigated. The effect of the amount and type of polymer on the physical properties and in vitro drug release was studied and compared to commercially available Ambroxol(?) SR capsules. A kinetic study of the release profile of AMX from the prepared matrix tablets was performed. All excipients used in the study were compatible with the model drug. AMX/drug mixtures containing sodium alginate (NA) and hydroxypropylmethyl cellulose (HPMC) showed better flow properties than other polymers used in the study. The in vitro drug release studies showed that matrix tablets formulae containing 10% HPMC (S7) or a combination of 30% NA and 5% HPMC (Ah) exhibited a higher ability to control the release of AMX. The kinetic study revealed that a diffusion controlled mechanism prevailed except when carbopol was used. Formula Ah followed a non-fickian diffusion mechanism similar to Ambroxol(?) SR capsules. Both formulae S7 and Ah could be considered as potential candidates for formulation of AMX controlled release matrix tablets.     

Controlled release reservoir mini tablets approach for controlling the drug release of Galantamine Hydrobromide

The objective of this study is to explore and investigate the reservoir mini tablets approach to control the release of Galantamine Hydrobromide in comparison to desired release profile to the Innovator formulation Razadyne ER capsules as disclosed in US Patent 7,160,559 which is granted to Janseen Pharmaceutica NV. The core mini tablets were prepared using the direct compression and wet granulation methods. These core mini tablets were further coated with Galantamine Hydrobromide in two different portions; 70% as controlled release and 30% as immediate release and then filled in empty hard gelatin capsule shells. The dissolution profiles of each formulation were compared to those of Razadyne ER capsules and the mean dissolution time (MDT), dissolution efficiency (DE%) and dissolution similarity (f2 factor) were calculated. It was observed that core formulation plays an important role in controlling the drug release as well as maintaining pH independent drug release profile. The release mechanism of GAH from reservoir mini tablet formulation follows Higuchi and first order. These results imply that controlled release reservoir mini tablets which further filled into empty hard gelatin capsule shells can be a suitable method to formulate controlled release Galantamine hydrobromide.     

In vitro release of valerenic and hydroxyvalerenic acids from valerian tablets

Although most commercial valerian formulations are coated tablets not any comparison study of their drug release profiles has been published so far. The main objective of this work is to establish a drug release test suitable for studying and comparing different valerian tablets. Thus, hydroxyvalerenic and valerenic acid concentrations were assayed by HPLC using a C18 Kromasil (200 x 4.6 mm, 5 microm) column and a mobile phase containing methanol and an orthophosphoric acid solution 0.5% v/v in water at a ratio of 75:25 at a constant flow rate of 1 ml/min. Saturation solubilities for hydroxyvalerenic and valerenic acid at pH 6.8 were 26 +/- 5.1 and 1 +/- 0.6 microg/ml, respectively. Usually for drugs with such low solubility values, their oral absorption and hence bioavailability are limited by their dissolution characteristics. A dissolution test was conducted according to the general method 2 (paddles) of USP 24 using 500 ml buffer medium (pH 6.8) at 50 rpm. Five different formulations were studied and compared: one uncoated tablet formulation and four marketed coated tablets. The uncoated tablet formulation had the fastest release profile, whereas the coated tablets manifested very different release patterns, depending on the type of formulation. Because of these differences in drug release pattern not every tablet formulation may be appropriate for the same clinical indications. Clinical data are required to confirm the correlation between drug release pattern and the therapeutically value of each formulation.     

吲哚美辛HP MCP肠溶片的制备及溶出度考察

以吲哚美辛为模型药物 ,采用本室新研制开发的肠溶材料羟丙甲纤维素邻苯二甲酸酯(HPMCP)包衣 ,制备了吲哚美辛肠溶片。通过考察吲哚美辛HPMCP包衣片的溶出度 ,并与吲哚美辛HP55(日本信越公司同类材料 )包衣片及 5种市售吲哚美辛肠溶片的溶出度进行比较来研究HPMCP包衣膜的性质。用相似因子法和chow’s法对溶出实验数据进行统计分析 ,结果表明HPMCP包衣片与HP55包衣片溶出行为完全相似 ,相似因子F2 =70 1 ( 5 0≤F2 ≤ 1 0 0 ) ,HPMCP包衣片片心药物溶出速率明显快于 5种市售片。     

In vitro characterization and release study of Ambroxol hydrochloride matrix tablets prepared by direct compression

A series of either hydrophilic or hydrophobic polymers were used to prepare controlled release Ambroxol hydrochloride (AMX) matrix tablets by direct compression. Both the compatibility and flow properties of AMX/polymer mixtures were investigated. The effect of the amount and type of polymer on the physical properties and in vitro drug release was studied and compared to commercially available Ambroxol^® SR capsules. A kinetic study of the release profile of AMX from the prepared matrix tablets was performed. All excipients used in the study were compatible with the model drug. AMX/drug mixtures containing sodium alginate (NA) and hydroxypropylmethyl cellulose (HPMC) showed better flow properties than other polymers used in the study. The in vitro drug release studies showed that matrix tablets formulae containing 10% HPMC (S7) or a combination of 30% NA and 5% HPMC (Ah) exhibited a higher ability to control the release of AMX. The kinetic study revealed that a diffusion controlled mechanism prevailed except when carbopol was used. Formula Ah followed a non-fickian diffusion mechanism similar to Ambroxol^® SR capsules. Both formulae S7 and Ah could be considered as potential candidates for formulation of AMX controlled release matrix tablets.     

Controlled release reservoir mini tablets approach for controlling the drug release of Galantamine Hydrobromide

The objective of this study is to explore and investigate the reservoir mini tablets approach to control the release of Galantamine Hydrobromide in comparison to desired release profile to the Innovator formulation Razadyne^® ER capsules as disclosed in US Patent 7,160,559 which is granted to Janseen Pharmaceutica NV. The core mini tablets were prepared using the direct compression and wet granulation methods. These core mini tablets were further coated with Galantamine Hydrobromide in two different portions; 70% as controlled release and 30% as immediate release and then filled in empty hard gelatin capsule shells. The dissolution profiles of each formulation were compared to those of Razadyne^® ER capsules and the mean dissolution time (MDT), dissolution efficiency (DE%) and dissolution similarity (f2 factor) were calculated. It was observed that core formulation plays an important role in controlling the drug release as well as maintaining pH independent drug release profile. The release mechanism of GAH from reservoir mini tablet formulation follows Higuchi and first order. These results imply that controlled release reservoir mini tablets which further filled into empty hard gelatin capsule shells can be a suitable method to formulate controlled release Galantamine hydrobromide.     

卡维地洛脉冲释放片的制备及体外释药特征

目的：制备卡维地洛脉冲释放片并考察其体外释药特征。方法：采用压制包衣法制备卡维地洛定时脉冲释放片,紫外分光光度法测定卡维地洛药物含量,以体外释放度为主要评价指标,考察崩解剂、包衣材料等对脉冲片释药性能的影响,并对处方进行优化。结果：处方中片芯含药量为10%,以63%的CMS-Na为崩解剂,27%的MCC为填充剂压制片芯;以35%的HPMC、62.5%的卡拉胶和1%的PEG 6000为衣膜材料,2.5%的滑石粉为润滑剂,粉末直接压片包衣。以pH4.0醋酸缓冲液为释放介质,包衣脉冲片时滞8 h后,累积释放度达80%以上。结论：卡维地洛压制包衣片能实现定时脉冲释药效果。     

Influence of Plasticizer Type and Coat Level on Surelease® Film Properties

Two commercially available formulations of aqueous ethylcellulose dispersion differing in their plasticizer, i.e., Surelease/E-7-7050 containing dibutyl sebacate (DBS) and Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC), were evaluated and compared for their film properties as a function of polymeric coat level. Ibuprofen tablets were coated at 1, 2, 3, and 5% w/w levels using each Surelease formulation, and the coated tablets were evaluated for their drug release characteristics, coat reflectivity (gloss), surface texture, Brinell hardness, and elastic modulus. The drug release was dependent on the coat level and followed Hixson–Crowell cube-root model at 1% coat level. However, at ≥2% coat levels, the release from tablets coated with GTC plasticized formulation appeared to be best described by non-Fickian release mechanism and that from tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release mechanism. At equal coat levels, tablets coated with GTC plasticized Surelease yielded lower drug release rates, higher reflectivity (gloss), lower surface roughness, higher Brinell hardness, and lower elastic modulus than those coated with DBS plasticized formulation. A good correlation was observed between the drug release rates and the reflectivity and surface texture of the coated tablets. The film-coats of GTC plasticized formulation were harder and more elastic than those of DBS plasticized formulation indicating better mechanical integrity.     

Formulation and evaluation of omeprazole tablets for duodenal ulcer

Omeprazole pellets containing mucoadhesive tablets were developed by direct punch method. Three mucoadhesive polymers namely hydroxypropylemethylcellulose K4M, sodium carboxy methylcellulose, carbopol-934P and ethyl cellulose were used for preparation of tablets which intended for prolong action may be due to the attachment with intestinal mucosa for relief from active duodenal ulcer. Mucoadhesive tablets were coated with respective polymer and coated with Eudragit L100 to fabricate enteric coated tablets. The prepared tablets were evaluated for different physical parameters and dissolution study were performed in three dissolution mediums like 0.1N hydrochloric acid for 2h, pH 6.5 and pH 7.8 phosphate buffer solution for 12hr. Sodium carboxymethylcellulose showed above 95% release within 10 h where as carbopol-934P showed slow release about 88% to 92% over a period of 12 h. having excellent mucoadhesive strength but ethyl cellulose containing tablets showed less than 65% release. The release mechanism of all formulation was diffusion controlled confirmed from Higuchi's plot. Thus, the present study concluded that, carbopol-934P containing mucoadhesive tablets of omeprazole pellets can be used for local action in the ulcer disease as well as for oral controlled release drug delivery.     

Influence of plasticizer type and coat level on Surelease film properties

Two commercially available formulations of aqueous ethylcellulose dispersion differing in their plasticizer, i.e., Surelease/E-7-7050 containing dibutyl sebacate (DBS) and Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC), were evaluated and compared for their film properties as a function of polymeric coat level. Ibuprofen tablets were coated at 1, 2, 3, and 5% w/w levels using each Surelease formulation, and the coated tablets were evaluated for their drug release characteristics, coat reflectivity (gloss), surface texture, Brinell hardness, and elastic modulus. The drug release was dependent on the coat level and followed Hixson-Crowell cube-root model at 1% coat level. However, at > or = 2% coat levels, the release from tablets coated with GTC plasticized formulation appeared to be best described by non-Fickian release mechanism and that from tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release mechanism. At equal coat levels, tablets coated with GTC plasticized Surelease yielded lower drug release rates, higher reflectivity (gloss), lower surface roughness, higher Brinell hardness, and lower elastic modulus than those coated with DBS plasticized formulation. A good correlation was observed between the drug release rates and the reflectivity and surface texture of the coated tablets. The film-coats of GTC plasticized formulation were harder and more elastic than those of DBS plasticized formulation indicating better mechanical integrity.     

Quality by design, part II: application of NIR spectroscopy to monitor the coating process for a pharmaceutical sustained release product

Ammonio methacrylate copolymers are commercially available as Eudragit RL/RS; they differ in the degree of quaternary ammonium group substitution, which gives them different permeabilities. These closely related polymers can be combined in various ratios to control release rate; consequently, release rate is controlled by the polymer composition and coating thickness. Therefore, predicting drug release from methacrylate copolymers using near infrared spectroscopy (NIRS) can be technically difficult. Thus, the objective of this study is to use NIRS to develop multivariate calibration models to predict tablet coat thickness and release rate for tablets coated with varying polymer ratios. A series of sustained release orbifloxacin formulations were developed with varying polymer ratios. Partial least squares (PLS) models were developed to predict coat thickness; samples from these formulations were pooled and a combined calibration was generated. To assess dissolution, tablets were coated using Eudragit RL and RS with ratios of 0:5, 1:4, 2:3, 3:2, 4:1, and 5:0. The amount released at set time-points was used to build PLS models. For the first time, NIRS has been successfully used to monitor Eudragit polymer coat thickness and drug release from tablets coated with various RL:RS ratios, which demonstrates the potential of NIRS as tool for coating process.     

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8-7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion)>Eudragit FS>Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.     

Once daily sustained release tablets of venlafaxine, a novel antidepressant.

Venlafaxine is a unique antidepressant that differs structurally from other currently available antidepressants. Sustained release tablets of venlafaxine to be taken once daily were formulated with venlafaxine hydrochloride equivalent to 75 mg of venlafaxine base. Matrix system based on swellable as well as non-swellable polymers was selected for sustaining the drug release. Different polymers viz. hydroxypropylmethylcellulose (HPMC), cellulose acetate, Eudragit RSPO, ethylcellulose etc. were studied. Combinations of non-swellable polymers with HPMC were also tried in order to get the desired sustained release profile over a period of 16 h. The effect of drug to polymer ratio on in vitro release was studied. The marketed formulation was evaluated for different parameters such as appearance, weight variation, drug content and in vitro drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. These were evaluated for appearance, weight variation, thickness, hardness, friability, drug content and in vitro drug release at selected time intervals. In vivo studies were carried out for the optimized formulation in 12 healthy human volunteers and the pharmacokinetic parameters were compared with the marketed one.     

Design and evaluation of floating multi-layer coated tablets based on gas formation

Floating multi-layer coated tablets were designed based on gas formation. The system consists of a drug-containing core tablet coated with a protective layer (hydroxypropyl methylcellulose), a gas forming layer (sodium bicarbonate) and a gas-entrapped membrane, respectively. The mechanical properties of acrylic polymers (Eudragit^® RL 30D, RS 30D, NE 30D) and ethylcellulose were characterized by the puncture test in order to screen a suitable film for the system. Eudragit^® RL 30D was chosen as a gas-entrapped membrane due to its high flexibility and high water permeability. The obtained tablets enabled to float due to the CO₂-gas formation and the gas entrapment by polymeric membrane. The effect of formulation variables on floating properties and drug release was investigated. The floating tablets using direct-compressed cores had shorter time to float and faster drug release than those using wet-granulated cores. The increased amount of a gas forming agent did not affect time to float but increased the drug release from the floating tablets while increasing coating level of gas-entrapped membrane increased time to float and slightly retarded drug release. Good floating properties and sustained drug release were achieved. These floating tablets seem to be a promising gastroretentive drug delivery system.     

Preparation of enteric coated timed-release press-coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting

As a new oral drug delivery system for colon targeting, enteric coated timed-release press-coated tablets (ETP tablets) were developed by coating enteric polymer on timed-release press-coated tablets composed of an outer shell of hydroxypropylcellulose and core tablet containing diltiazem hydrochloride (DIL) as a model drug. The results of the in vitro dissolution tests in JP 1st fluid (pH 1.2) and JP 2nd fluid (pH 6.8) indicated that these tablets showed both acid resistance and timed-release. To clarify whether ETP tablets could have been of use in the gastrointestinal tract, ETP tablets with a layer of phenylpropanolamine hydrochloride (PPA) (a marker of gastric emptying) between the enteric coating layer and outer shell were prepared, and were administered to beagle dogs. The gastric emptying time and lag time after gastric emptying were evaluated by determining the times at which PPA and DIL first appeared in the plasma (TFA(PPA) and TFA(DIL), respectively). TFA(PPA) and TFA(DIL) were about 4 and 7 h, respectively. This value of TFA(PPA) indicated that ETP tablets displayed acid resistance in the stomach as well as in JP Ist fluid. Subtraction of TFA(PPA) from TFA(DIL) gave a value of about 3 h which agreed well with the lag time determined by in vitro dissolution test in JP 2nd fluid. Also, the results seemed to be in accordance with the time at which the tablets reached the colon after gastric emptying. Therefore, ETP tablets seemed to be an effective tool for oral site-specific delivery including targeting of the colon.     

盐酸地尔硫爆破型脉冲控释片研究

目的以盐酸地尔硫为(diltiazem hydrochloride,DIL)模型药物,研制爆破型脉冲控释片并考察其体内外脉冲释药特性。方法以乙基纤维素和丙烯酸树脂(Eudragit L)为包衣材料,采用薄膜包衣法,制备含盐酸地尔硫60 mg的脉冲控释片。通过体外释放度实验,考察了处方因素对脉冲控释片体外释放的影响;通过吸水实验确定了脉冲控释片的释药机理;以高效液相色谱法测定8名受试者的体内血药浓度,研究脉冲控释片的体内药代动力学和生物利用度。结果片芯处方、包衣组成和包衣厚度影响盐酸地尔硫的脉冲释放。该制剂在体外延迟释放时间T₁₀为4.4 h,释放至最大的时间T_rm为8.0 h,脉冲释放时间T_rm-10为3.6 h;其体内的延迟释放时间T_lag为4.9 h,达峰时间T_max为8.0 h,从开始释放到达峰的时间T_psi为3.1 h。脉冲控释片的相对生物利用度为105%。结论盐酸地尔硫爆破型脉冲控释片在体内外都具有脉冲释放特性。     

A new deferiprone controlled release system obtained by ultrasound-assisted compression

Abstract

Objectives: This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per day.

Methods: Binary matrix tablets containing deferiprone and thermoplastic polymers have been prepared using an ultrasound-assisted tableting machine. Scanning electron microscopy has been employed to determine a sintering phenomenon of the excipients. Water uptake and drug release studies have been carried out to evaluate the ability of the polymers to control the drug release.

Results: SEM micrographs showed that some polymers underwent the sintering process and the in vitro dissolution test showed good fit of the release data from these tablets to the zero-order kinetic model.

Conclusions: Carbopol 974P and 971P have been selected as matrix forming polymers for the final formulation. The polymer percolation threshold has been exceeded with 15% w/w of polymer. Therefore, sustained release tablets have been developed with only 15% of excipient. This implies that matrix tablets containing 750?mg of API, intended for two administrations a day, can be obtained with a similar weight to those existing in the market containing 500?mg of API for three administrations a day.     

Optimization of pH-independent release of nicardipine hydrochloride extended-release matrix tablets using response surface methodology

The purpose of this study was to optimize the pH-dependent release of nicardipine hydrochloride extended release formulations by using simultaneously combination two hydrophilic polymers: hydroxypropylmethylcellulose (HPMC) and sodium alginate as retardant and avicel as additive. The constrained mixture experimental design was used to prepare systematic model formulations which were composed of three formulation variables: the content of HPMC (X1), avicel (X2), and sodium alginate (X3). The response surface methodology (RSM) and multiple response optimization utilizing the polynomial equation were used to search for the optimal formulation with specific release rate at different time intervals and to quantify the effect of each formulation variables. The drug release percent at 3, 6 and 12 h were the target responses and were restricted to 10-30% (Y3h), 40-65% (Y6h) and not less than 80% (Y12h), respectively. The results showed that the effect of combination of HPMC and sodium alginate was the most influence factor on the drug release from extended-release matrix tablets. The observed results of Y3h, Y6h and Y12h coincided well with the predictions in the RSM optimization technique, indicating it was quite useful for optimizing pharmaceutical formulation. The mechanism of drug release from extended-release matrix tablets was dependent on the added amount of alginate. The release kinetic of drug from HPMC matrix tablets with alginate was followed the zero-order release pattern.     

硫酸特布他林脉冲控释片的制备与释放机理研究硫酸特布他林脉冲控释片的制备与释放机理研究

目的制备硫酸特布他林双层包衣脉冲片，考察处方及释放条件对体外释药行为的影响，解析其释放机理。方法粉末直接压片法制备含渗透活性物质的片芯，滚转包衣锅法分别包溶胀层和控释衣层。通过测定释放度研究脉冲片的制剂学特征，并研究脉冲片的吸水动力学和膨胀行为。结果双层包衣片以脉冲形式释放，释药时滞随控释衣层厚度增加而延长，释药速度减小；渗透活性物质和溶胀层可提高快速释放期的释药速率。溶出介质pH值和搅拌速度对释药行为无影响。释药机理包括扩散、溶胀和渗透泵原理。结论调整控释衣膜厚度和组成可获得理想的脉冲释药行为，满足时辰治疗的要求。     

盐酸地尔硫爆破型脉冲控释片研究

目的　以盐酸地尔硫为 (diltiazemhydrochloride,DIL)模型药物 ,研制爆破型脉冲控释片并考察其体内外脉冲释药特性。方法　以乙基纤维素和丙烯酸树脂 (EudragitL)为包衣材料 ,采用薄膜包衣法 ,制备含盐酸地尔硫6 0mg的脉冲控释片。通过体外释放度实验 ,考察了处方因素对脉冲控释片体外释放的影响 ;通过吸水实验确定了脉冲控释片的释药机理 ;以高效液相色谱法测定 8名受试者的体内血药浓度 ,研究脉冲控释片的体内药代动力学和生物利用度。结果　片芯处方、包衣组成和包衣厚度影响盐酸地尔硫的脉冲释放。该制剂在体外延迟释放时间T1 0 为 4 4h ,释放至最大的时间Trm 为 8 0h ,脉冲释放时间Trm - 1 0 为 3 6h ;其体内的延迟释放时间Tlag为 4 9h ,达峰时间Tmax为 8 0h ,从开始释放到达峰的时间Tpsi为 3 1h。脉冲控释片的相对生物利用度为 10 5 %。结论　盐酸地尔硫爆破型脉冲控释片在体内外都具有脉冲释放特性。