Release Retardant Research Articles

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control.

Coated drug pellets enjoy widespread use in hard gelatine capsules. In heterogeneous pellets, the drug substance is layered onto core pellets. Coatings are often applied to generate a retarded release or an enteric coating. In the present study, the thickness of a polymer coating layer on drug pellets was correlated to the drug release kinetics. The question should be answered whether it is possible to stop the coating process when a layer thickness referring to an intended drug release is achieved. Inert pellets were first coated with sodium benzoate and second with different amounts of water insoluble polyacrylate in a fluidized bed apparatus equipped with a Wurster inlet. The whole process was controlled in-line and at-line with process analytical technology by the measurement of the particle size and the layer thickness. The in-vitro sodium benzoate release was investigated, and the data were linearized by different standard models and compared with the polyacrylate layer thickness. With increasing polyacrylate layer thickness the release rate diminishes. The superposition of several processes influencing the release results in release profiles corresponding approximately to first order kinetics. The coating layer thickness corresponds to a determined drug release profile. The manufacturing of coated drug pellets with intended drug release is possible by coating process control and layer thickness measurement. Preliminary investigations are necessary for different formulations.

Development of Chitosan-Maize Starch based Co-processed excipient: As release retardant material

In the present study, co-processed excipients from chitosan, and maize starch were prepared by co-dispersion, and co-granulation methods in 1:1 ratio. The resultant products were then characterized physically by their micrometric properties and hygroscopic characters. The co-processed excipient prepared by co-granulation was chosen and was added to a directly compressible oral sustained-release tablet (Batch F1-F4) containing ibuprofen as a model drug. A well-known marketed ibuprofen tablet (Motrin) was taken for comparison purposes of the dissolution characteristics. Pre-compression parameters, as well as post-compression parameters of all the batches, were performed. The pre-compression parameters, and post-compression parameters of F3, containing chitosan to maize in the ratio of 2:1, were found to be comparable with the marketed product. F3 batch showed 74.7 % of drug release up to 8 h, which reflect the release retardant properties of co-processed excipient. Collectively, co-processed excipients of chitosan, and maize starch improve the physical properties of individual materials, and can be used as a directly compressible excipient as a release retardant material for oral sustained-release tablets.

Formulation and Evaluation of Sustained Release Dosage Form of Venlafaxine Hydrochloride for Enhanced Treatment of Neurodisorders

In the present study, we have designed and developed a sustained-release tablet formulation of Venlafaxine Hydrochloride. The optimized formulation was then subjected to various evaluation parameters. The formulation of venlafaxine hydrochloride sustained release tablets with a dosage of 500 mg included the utilization of several hydrophilic polymers, including jackfruit mucilage, HPMC K4, and PVPK30, as release retardants. This was done to extend the duration of drug release to 12 hours. The formulation features, including pre-compression and post-compression investigations, were conducted individually according to established protocols. The tablets were determined to be compliant in terms of weight uniformity, hardness, thickness, diameter, friability, and drug content. Separate in-vitro dissolution studies were done for both tablets. The venlafaxine hydrochloride SR formulation F18 was optimized to provide the desired release profile for up to 12 hours. The Venlafaxine Hydrochloride SR formulation was optimized and exhibited zero-order release kinetics. The stability studies conducted under accelerated conditions at a temperature of 40 ± 2°C and a relative humidity of 75 ± 5% yielded good results. The study indicated that the sustained release administration of Venlafaxine HCl is potentially efficacious. It reduces the frequency at which the patient has to take medication and improves patient adherence. Our objective is to conduct in-vivo pharmacokinetic studies of the formulation to verify the drug’s entry into the systemic circulation.

Optimization In-vitro Evaluation and Scratch Wound Healing Assay of Hexacosane Topical Gel for Wound Healing.

The compounds hexocosane, a sterol hydrocarbon identified in the dichloromethane extract and isolated from marine sponges of the genus Agelas. Hexocosane possesses anti-inflammatory and antioxidant activities that reduce inflammation and oxidative stress, they promote cell proliferation and angiogenesis, facilitating tissue regeneration and repair. This multifaceted approach makes this secondary metabolite a promising candidate for developing advanced wound care therapies that effectively address both infection control and wound healing. On the basis of viscosity, in-vitro release, and skin retention, optimal gel formulations were developed with hexocosane (1%) to achieve the best results. A response surface methodology Box-Behnken design was applied on three factors and three levels [carbopol 940 (1, 1.25 and 1.5%), hydroxypropyl methylcellulose (HPMC) (1,1.5 and 1.2%), and propylene glycol (0–1–1.5% and 1–2%, respectively] using three factors and three levels. In order to assess the spreadability and viscosity, a glass slide and a Brookfield viscometer were used. An assay was conducted to determine how topical gel affects wound healing. The optimization study of the gel formulation, involving variations in adhesive polymer (Carbopol 940), release retarding polymer (HPMC K4M), and penetration enhancer (Surfactant), has identified three noteworthy formulations (F4, F8 & F14). Each formulation is characterized by specific attributes such as viscosity, in-vitro drug release, and skin retention. All samples were found to elicit significant wound healing efficacy as evidenced from the representative photomicrographs. The maximum efficacy was elicited by formulation (F4) with 100 mg drug at the time duration of 36 hours.

Formulation and evaluation of Mesalamine mini-tablets in enteric-coated capsule for the treatment of ulcerative colitis using a factorial design approach

The Enteric Capsule Drug Delivery Technology (ECDDT) was designed to enable oral administration while ensuring complete enteric protection and swift release in the upper gastrointestinal (GI) tract, without the need for coatings. Current study used a 32factorial design (Stat-Ease Design Expert v12) to formulate a mini-tablet in an enteric-coated capsule to treat ulcerative colitis utilising ECDDT and mini-tablets. Mesalamine, an amino salicylate, was used as a model drug to study the effects of independent variables like HPMC K4M as a release retarding polymer at 10-20% and Crospovidone as a super disintegrant at 2-5% on in vitro drug release to meet desired Q points of dissolution. higher value of Tmax (10 Hours) and T1/2 (9 Hours) was observed for the Optimized formulation with Cmax value of (35.24 ± 0.45 ng/mL), AUC (0-48) (411.58 ± 1.45 hr.ng/mL) and Ke (0.077 ± 0.010 hr-1) it may be due to delayed release formulation.

Formulation and Evaluation of Transdermal Patches of Metformin Hydrochloride using HPMC K100 as Release Retarding Agent

Formulation and Evaluation of Transdermal Patches of Metformin Hydrochloride using HPMC K100 as Release Retarding Agent

Formulation and Evaluation of Extended Release Matrix Tablets of Lamotrigine

For extended release drug delivery systems, the oral route of drug administration has, by far received more attention as it is natural uncomplicated, convenient and safer route. Matrix tablets composed of drug and release retarding material (e.g. polymer) offer the simplest approach in designing the extended release system. Long-term adherence to anti-epilepsy drug (AED) regimens is frequently suboptimal. Poor adherence to therapy is associated with a number of negative consequences, including an increase in patient seizures and mortality. The present study was aimed to study the effect of Chitosan and Sodium Alginate on the release rate Lamotrigine for the preparation of extended release formulations. Matrix Tablets were prepared by wet granulation method and subjected for Physiochemical and in-vitro evaluation tests. The results were shown that the prepared were found to be within the pharmacopeial limit and with good release characteristics.

Study on Natural Gums and Resins as Release Retarding Agents in Development of Sustained Release Matrix Tablets of Didanosine

Didanosine is an anti-retroviral drug which helpful in preventing human immunodeficiency virus (HIV) from multiplication in the body. This drug has a relatively short half-life and low absolute bioavailability and requires frequent dosing. So to avoid this frequent dosing and to improve the patient’s compliance, the development of sustained-release tablets is necessary. Natural gums and resins play an important role in retarding drug release. Didanosine extended-release matrix formulations developed with wet granulation using gum kondagogu, guar gum, gum olibanum, and olibanum resin, and evaluated for pre and post-compression parameters. The outcome of all evaluation tests is reached IP specifications. Formulations with kondagogu F1-F3 failed to extend the drug release. F4-F6 was formulated with gum kondagogu and guar gum, in which F4 prolonged the release up to 12 hours with 98.23%. The formulations F7 with olibanum resin release 96.13%, and F10 with gum olibanum releases 93.15% drug at the end of 12 hours. The conclusion from the study was that natural polymers could be used to enhance drug release for an extended period.

Formulation, design, and evaluation of valsartan sodium-sustained-release matrix tablets

The main aim of present work was to formulate and evaluate sustain release matrix tablets of Valsartan, an angiotensin II Receptor type 1 antagonist. Sustain release formulation are those which delivers the drug locally or systemically at a predetermined rate for a fixed period of time. The matrix tablet was prepared by direct compression method using by various concentration of chitosan and sodium alginate with combination of various release retardant polymer. The powder mixtures were subjected to various pre-compression parameters such as angle of repose, bulk density, tapped density and Carr’s index shows satisfactory result and the compressed tablets are evaluated for post-compression parameters such as weight variation, thickness, hardness, friability, drug content, in-vitro dissolution and stability studies. In-vitro dissolution studies were carried out for 24 hours using 0.1N HCl for first 2 hours and pH 6.8 phosphate buffers for 24 hours and the result showed that formulations F4 and F7 showed good dissolution profile to control the drug release respectively. Formulation containing higher concentration of chitosan and sodium alginate along with polymers sustainedthedrugreleasefor theperiodof24hours.The compatibilityof thedrug, polymers and other excipients were determined by FT-IR Spectroscopy. Results showed that the drug was compatible with polymers and other excipients. The release data was fitted to various mathematical models such as Zero-order, First-order, Higuchi equation and Korsmeyer- Peppas model to evaluate the kinetics and the drug release. The drug release followed first order and the mechanism was found to be non-Fickian. The stability studies were carried out for 3 months and result indicates that the selected formulations (F4and F7) were stable.

FORMULATION AND EVALUATION OF LOSARTAN POTASSIUM MATRIX TABLETS BY USING DIFFERENT POLYMERS

The study aims to create a sustained release matrix tablet for Losartan potassium, an angiotensin II receptor antagonist, to improve patient compliance and maintain therapeutic blood or tissue levels for extended periods. The research investigates the role of novel semi-synthetic polymers and natural polymers in comparison to well-known release retarding agents. Gastroretentive drug delivery systems (GRDDS) are unique technologies designed to improve drug bioavailability and absorption by avoiding the first-pass effect. Losartan potassium, an angiotensin II receptor antagonist, has a bioavailability of 32% and a low elimination half-life, making it suitable for oral controlled release. The study utilized natural and synthetic polymers in matrix tablet preparation, concentration, drug particles size, additives, and excipients to modify drug release. The powder mixtures were tested for pre-compression parameters and post-compression parameters, and in-vitro dissolution studies showed good dissolution profiles for drug release. Formulations with higher concentrations and polymers sustained drug release for 24 hours. FT-IR Spectroscopy confirmed drug compatibility with polymers and other excipients KEYWORDS: matrix tablets, Losartan Potassium, flow properties, pre compression parameters post compression parameters, In-vitro dissolution.

In-vivo study of Budesonide mini-tablets in enteric coated capsules for the treatment of ulcerative colitis

Budesonide, a corticosteroid, was used as a model drug to study the effects of independent variables like HPMC K4M as a release retarding polymer at 2-6% and Crospovidone as a super disintegrant at 2-5% on in vitro drug release to meet desired Q points of dissolution. Current study used a 32 factorial design (Stat-Ease Design Expert v12) to formulate a mini-tablet in an enteric-coated capsule to treat ulcerative colitis utilising ECDDT and mini-tablets. An in vivo study was conducted in New Zealand rabbits to determine the pharmacokinetic parameters for the optimized formulation (BF4-O). Time vs. plasma concentration plots of the Pure drug and Optimized formulation was observed. Plotted Area under the curve indicates the extent of drug absorption inside the body. Pharmacokinetic analysis of Budesonide pre drug plasma concentration–time data provided the following pharmacokinetic parameters like Cmax value ranging (1.42 ± 2.12 ng/mL), Tmax value (4.0 Hours), AUC value (12.77 ± 0.15 h.ng/mL), Half Life (3.5 Hours) and other pharmacokinetic parameters are depicted. Study demonstrates the variability in pharmacokinetic parameters like Tmax, Cmax, T1/2 (Hours), AUC and Ke. Henceforth, the newly developed Mini-Tablet in Enteric Coated capsule could be utilized clinically for the treatment of Ulcerative Colitis, alternatively with cost-effectiveness.

Formulation and Evaluation of Floating Microspheres

Gastro-retentive dosage forms have potential for use as controlled- release drug delivery systems. Gastro retentive floating drug delivery systems have a bulk density lower than that of gastric fluids and thus increase residence time of drug in stomach and provide controlled delivery of many drugs. The aim of the present study is formulation and characterization of floating microspheres using model drug. Floating microspheres were prepared by oil-in-water emulsion solvent evaporation technique using ethyl cellulose as release retarding polymers. The floating microspheres were evaluated for percentage yield (%), particle size, drug content, drug entrapment efficiency, in-vitro floating ability and in-vitro drug release studies. The surface morphology of prepared microspheres was characterized by scanning electron microscopy. The microspheres were found to be spherical in shape and porous in nature. Compatibility studies were performed by fourier transform infrared (FTIR) technique. The prepared microspheres showed prolonged drug release of 12 h and remain buoyant for more than 12 h. In-vitro release kinetics were studied in different release kinetics models like zero order, first order model. It was concluded that developed floating microspheres offers a suitable and practical approach for prolonged release of drug over an extended period of time and thus oral bioavailability, efficacy and patient compliance is improved

Exploring the potential of neem and tamarind gum as release retardants: Design and statistical optimisation of vildagliptin extended release matrix systems using D-optimal quadratic mixture design

Exploring the significant role of natural polymers in developing drug delivery systems has been a promising area of research interest. The current investigation uses a D-optimal quadratic mixture design to design and evaluate neem and tamarind gum-based vildagliptin extended-release matrix tablets. Studying the combination effect of gums is one of the major objectives. Initial screening studies were performed to select the factors and their levels. The variables selected at different levels in mg/tablet are neem gum, tamarind gum, polyvinylpyrrolidone, and lactose monohydrate. Based on the screening experiments with both gums, the polymer content of 165 mg was chosen as the highest level in the DOE. Nineteen runs were generated to screen the desired parameters as responses. The total weight of the formulation was kept constant at 275 mg. Time (hours) required for 50 %, 90 % and 100 % of drug release and tablet hardness were selected as the responses for each run. The wet granulation method was adopted, and the critical variables were optimised using the design of experiments following Design Expert software. Statistical analysis was conducted, and the optimised formulations were prepared and evaluated to compare with the predicted responses. Stability studies were performed for the optimised batches. Results indicated that the prepared batches met the compendial limits and confirmed the application of neem and tamarind gum in the development of extended-release tablets of vildagliptin for 24 h. An optimised formulation comprising of 16.52 mg of neem gum and 148.48 mg of tamarind gum with a hardness of 7.5–8.5 kp produced 50 %, 90 % and 100 % drug release in 12, 22 and 25 h.

Citric acid cross-linking of a hydrogel from Aloe vera (Aloe barbadensis M.) engenders a pH-responsive, superporous, and smart material for drug delivery.

The current research work is based on the evaluation of a citric acid (CA) cross-linked Aloe vera (Aloe barbadensis M.) leaf hydrogel (CL-ALH) for pH-dependent and sustained drug release application. The CA was used in different concentrations (1.25, 2.5, 5.0, and 10.0%) to cross-link the ALH using homogenous reaction conditions. The synthesis of CL-ALH was confirmed through Fourier transform and nuclear magnetic resonance spectroscopic studies. The thermal analysis indicated that the ALH and CL-ALH were stable and decomposed in two steps. The scanning electron microscopic images of CL-ALH confirmed its porous nature due to the presence of interconnected channeling. The swelling of CL-ALH was evaluated at pH 1.2, 6.8, and 7.4 as well as in deionized water (DW). High swelling of CL-ALH was observed in DW, and at pH 7.4 and 6.8 whereas, less swelling of CL-ALH was witnessed at pH 1.2. CL-ALH also exhibited swelling/deswelling behavior in DW and ethanol, DW and normal saline, and at pH 7.4 and 1.2. Tablets were prepared from CL-ALH as a release retarding agent demonstrating the sustained release of venlafaxine hydrochloride (VFX) for 8 h. Whereas, VFX was released within 4 h from the ALH-based tablet formulation (un-cross-linked material) indicating the prolonged and sustained release behavior of CL-ALH. The VFX was released from CL-ALH tablets and followed zero-order kinetics. The mechanism followed by VFX release from CL-ALH tablets was non-Fickian diffusion. The in vivo fate of the tablet formulation was observed through an X-ray study. The CL-ALH-based tablet safely passed through the stomach of a stray dog without any significant erosion and then disintegrated in the small intestine and colon. These findings confirmed that the CL-ALH is an effective excipient for designing a sustained-release drug delivery system for the small intestine and colon.

Development of Modified-Release Diclofenac Sodium Capsules Using Blends of Pectin-Clay Multiparticulate Hybrid Systems as Release Retardants

A combination of inorganic and organic hybrid systems is of high research interest as they provide novel hybrid systems for the improvement of existing properties, overcoming limitations of the parent materials, and for the optimization of their controlled release potential. This study sorted to develop and pharmaceutically assess the release profile of diclofenac sodium using cocoa pod husk (CPH) blended with different proportions of either talc or bentonite as multiparticulate composite release modifiers. Preformulation investigations of the multiparticulate hybrid systems included pH, swelling index, moisture content, elemental contents, and flow properties. The FTIR was also used to investigate the compatibilities between pectin and bentonite (PB), pectin and talc (PT), and diclofenac and pectin-talc (DPT), as well as diclofenac and pectin-bentonite (DPB). The diclofenac content, uniformity of the weight of capsules, in vitro drug release, and the kinetics and mechanism of release of diclofenac from the hybrid systems were also investigated using mathematical models. The pectin yield was 23.3%, with the water-holding capacities of pectin-talc (PT) and pectin-bentonite (PB) hybrid systems being 6.4% and 5.0%, respectively. The swelling indices of PT and PB were 110.0 and 130.0 in 0.1 M HCL at pH 1.2 and 130.0 and 149.0 in phosphate buffer at pH 6.8, respectively. This system was also found to exhibit excellent flow properties, and there were no diclofenac-excipient interactions. All formulated batches passed the pharmacopoeial and nonpharmacopoeial tests. They also demonstrated controlled release properties via different release kinetics and mechanisms. This study shows that the pectin-talc and pectin-bentonite multiparticulate composites could be used as release modifiers in pharmaceutical preparations.

Potentials of Sterculia tragacantha Lindl seed husk gum as a release modifier in matrix tablet formulation

Natural gums have been utilized severally in the design of matrix tablets, either in their native or modified forms. The primary objective of this work was the extraction, characterization and utilization of the seed husk gum from Sterculia tragacantha Lindl as a release modifier in theophylline matrix tablets. Gum was extracted from the fresh seed husk of Sterculia tragacantha and tablet formulated via wet granulation. Drug-polymer compatibility was determined by FTIR and DSC while formulated tablets were evaluated for their in vitro dissolution release profile in two media, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) and compared with a commercial brand. Extracted gum powder presented a poor flow which improved on granulation, had a better swelling index and water holding capacity than tragacanth gum. Formulated tablets passed standard tablets test and sustained theophylline release up to 90.97 % and 88.09 % in SGF and SIF respectively at the twelfth hour. Drug release kinetics was by zero order in SGF via non-fickian diffusion. S. tragacantha seed husk gum presented a promising potential as a release retarding agent.

Formulation and Evaluation of Nifedipine Bilayer Floating Tablets

In the present investigation concern, the formulation and evaluation of bilayer floating tablet of Nifedipine which after an oral administration increase gastric residence time, to increase the bioavailability. Nifedipine is the Calcium channel blocker of the dihydropyridine type which used in angina pectoris and hypertension. It has a half-life of 2-4hours and bioavailability of 45-56%. It is advantageous to formulate bilayer floating tablet of Nifedipine helps to increase bioavailability, reduce dosing frequency, and reach maximum plasma concentration rapidly. Bilayer floating tablets comprised of two layers, immediate and sustain release layers. The immediate release layer is comprised of super disintegrating agent Karaya gum, and sustain release layer comprised of low density release retardant polymers like HPMC K4M and Guar gum; and sodium bicarbonate and citric acid gas generating agents. The prepared powder mixtures were subjected to FT-IR for all interaction. The tablets were prepared by direct compression. First, the powder blends of sustained release layer was pre-compressed and then powder blends of immediate release layer was added. Hardness, friability, drug content, floating lag time, total floating time, swelling index and in-vitro drug release were evaluated. In the present study, it was found that formulation F4 containing HPMC K4M and Guar gum in the ratio of 2:1 showed maximum drug release. The release data were adjusted to various mathematical models such as Higuchi, 1st order and zero order to evaluate the kinetics and mechanisms of the drug release and it was best suited for the Higuchi model. There were no notable changes in stability studies.

Quality by Design Approach for Optimization of Microbial and pH-Triggered Colon-Targeted Tablet Formulation Using Carboxymethyl Tamarind Gum.

ABSTRACT The purpose of this study was to apply the quality by design (QbD) approach in the development of a microbial and pH-triggered colon-targeted budesonide tablet. A retrospective research strategy was used to select various polysaccharide-based natural gums such as tamarind gum, gellan gum, karaya gum, gum ghutti, and khaya gum, which were then evaluated for their effectiveness in microbial degradation and targeting the colon. Viscosity profiles were generated in the presence of a prebiotic culture medium prepared by using the Velgut capsule that mimicked the impact of 4% rat cecal content and helpful in screening of natural polymer. Based on the cumulative drug release data of preliminary batches, carboxymethyl (CM) tamarind gum was identified as a superior and an excellent polymer over the tamarind gum for formulation development. The presence of water as a bridging agent in wet granulation also played an important role in the retardation of drug release. Tablets were supercoated with the enteric polymer, Eudragit S100. The Box-Behnken design was utilized, where the selected independent variables were the proportion of CM tamarind gum, % water proportion, and % weight gain of Eudragit S 100 to optimize the formulation. The optimized design space was generated with the criteria that a drug release should be of less than 5% within the first 2 h, less than 10% within the first 5 h, and more than 70% within the first 8 h, to achieve colon targeting. The optimized batch F3 was found stable as per International Council for Harmonisation guidelines. The roentgenography study for optimized formulation demonstrated that it remained intact for 5 h and, at 7 h, was disseminated completely. CM tamarind gum is efficient for colon targeting, and its proportion in 100 mg along with an enteric coating of 6% led to the optimized formulation.

Formulation, Development and Investigation of Matrix Type Sustained Release Tablet of Antiulcer Drug by Using Soluble Polymer as a Drug Release Retarding Agent

The main goals of sustained release drug delivery are to modify the medication's biopharmaceutical, pharmacokinetic, and pharmacodynamic properties in order to lessen adverse effects, increase patient compliance, and treat the illness. The current work set out to create sustained release tablets of nizatidine (220 mg) using a wet granulation process and different concentrations of polymers such as chitosan, Kollidon SR, and HPMC K100M. Pre-formulation characteristics were examined, including medication DSC analysis and FTIR research. We assessed a number of post-compression characteristics, including content homogeneity, thickness, hardness, friability, and weight uniformity. This study demonstrated how the post-compression characteristics of the drug formulation are influenced by the concentration of polymers.

Extraction, physicochemical characterization, functionality, and excipient ability of corn fiber gum-starch isolate from corn milling industry waste

Corn processing industries generate an extensive fibrous byproduct consisting of corn fiber gum (CFG) and residual starch (S). The present study hypothesized that CFG and S could be isolated as a single crosslinked conjugate. The isolated CFG-S conjugate was acidic, with a pKa value of 11.49, and a swelling index of 99.60%. Henderson–Hasselbalch equation predicted negligible ionization throughout the gastrointestinal pH range. The DSC thermogram highlights glass transition and temperature-specific structure stabilization through the exothermic crystallization domain. FTIR, SEM & XRD confirmed the structural conjugation and integrity of the conjugate. Tablets containing Venlafaxine hydrochloride as a model drug were prepared using CFG-S (14 and 57%) as excipient by wet granulation method. Percentage cumulative drug release with low concentration was up to 99.67175 ± 0.09 % in 5 h whereas with high concentration, it was extended to 12 h (P < 0.05). Korsemayer-Peppas release exponent indicates zero order (R2 = 0.9935) kinetics with super case-II anomalous transport showing diffusion and erosion as drug release mechanisms. The results confirmed that CFG-S isolate could act as a good binding agent at low concentrations and release extending cross-linked matrix former at a higher concentration for release retardant excipient.