Duloxetine HCl Lipid Nanoparticles: Preparation,Characterization, and Dosage Form Design

Solid lipid nanoparticles (SLNs) of duloxetine hydrochloride (DLX) were prepared to circumvent the problems of DLX, which include acid labile nature, high first-pass metabolism, and high-dosing frequency. The DLX-SLNs were prepared by using two different techniques, viz. solvent diffusion method and ultrasound dispersion method, and evaluated for particle size, zeta potential, entrapment efficiency, physical characteristics, and chemical stability. Best results were obtained when SLNs were prepared by ultrasound dispersion method using glyceryl mono stearate as solid lipid and DLX in ratio of 1:20 and mixture of polysorbate 80 and poloxamer 188 as surfactant in concentration of 3%. The mean particle size of formulation and entrapment efficiency was 91.7 nm and 87%, respectively, and had excellent stability in acidic medium. Differential scanning calorimetry and X-ray diffraction data showed complete amorphization of DLX in lipid. In vitro drug release from SLNs was observed for 48 h and was in accordance with Higuchi kinetics. In vivo antidepressant activity was evaluated in mice by forced swim test. DLX-SLNs showed significant enhancement in antidepressant activity at 24 h when administered orally in comparison to drug solution. These results confirm the potential of SLNs in enhancing chemical stability and improving the efficacy of DLX via oral route. The SLN dispersion was converted into solid granules by adsorbing on colloidal silicon dioxide and characterized for particle size after redispersion, morphology, and flow properties. Results indicated that nanoparticles were successfully adsorbed on the carrier and released SLNs when dispersed in water.     

Product Development Studies on Surface-Adsorbed Nanoemulsion of Olmesartan Medoxomil as a Capsular Dosage Form

The present study aimed at development of capsular dosage form of surface-adsorbed nanoemulsion (NE) of olmesartan medoxomil (OLM) so as to overcome the limitations associated with handling of liquid NEs without affecting their pharmaceutical efficacy. Selection of oil, surfactant, and cosurfactant for construction of pseudoternary phase diagrams was made on the basis of solubility of drug in these excipients. Rationally selected NE formulations were evaluated for percentage transmittance, viscosity, refractive index, globule size, zeta potential, and polydispersity index (PDI). Formulation (F3) comprising of Capmul MCM® (10% v/v), Tween 80® (11.25% v/v), polyethylene glycol 400 (3.75% v/v), and double-distilled water (75% v/v) displayed highest percentage cumulative drug release (%CDR; 96.69 ± 1.841), least globule size (17.51 ± 5.87 nm), low PDI (0.203 ± 0.032), high zeta potential (−58.93 ± 0.98 mV), and hence was selected as the optimized formulation. F3 was adsorbed over colloidal silicon dioxide (2 ml/400 mg) to produce free-flowing solid surface-adsorbed NE that presented a ready-to-fill capsule composition. Conversion of NE to surface-adsorbed NE and its reconstitution to NE did not affect the in vitro release profile of OLM as the similarity factor with respect to NE was found to be 66% and 73% respectively. The %CDR after 12 h for optimized NE, surface-adsorbed NE, and reconstituted NE was found to be 96.69 ± 0.54, 96.07 ± 1.76, and 94.78 ± 1.57, respectively (p > 0.05). The present study established capsulated surface-adsorbed NE as a viable delivery system with the potential to overcome the handling limitations of NE.KEY WORDS: bioavailability, nanoemulsion, olmesartan medoxomil, oral     

Buccal Dosage Forms: General Considerations for Pediatric Patients

The development of an appropriate dosage form for pediatric patients needs to take into account several aspects, since adult drug biodistribution differs from that of pediatrics. In recent years, buccal administration has become an attractive route, having different dosage forms under development including tablets, lozenges, films, and solutions among others. Furthermore, the buccal epithelium can allow quick access to systemic circulation, which could be used for a rapid onset of action. For pediatric patients, dosage forms to be placed in the oral cavity have higher requirements for palatability to increase acceptance and therapy compliance. Therefore, an understanding of the excipients required and their functions and properties needs to be particularly addressed. This review is focused on the differences and requirements relevant to buccal administration for pediatric patients (compared to adults) and how novel dosage forms can be less invasive and more acceptable alternatives.     

Ibuprofen-Loaded Calcium Stearate Pellets: Drying-Induced Variations in Dosage Form Properties

Pellets intended for oral dosing are frequently produced via extrusion/spheronization followed by drying. Typically, the last active process step, i.e., drying, is assumed to have little effect on the final dosage form properties (e.g., dissolution characteristics). Thus, there exist only a few studies of this subject. In the present study, calcium stearate/ibuprofen pellets were used as model system to investigate the impact of the drying conditions. Lipophilic calcium stearate matrix pellets containing 20% ibuprofen were prepared via wet extrusion/spheronization. Subsequently, desiccation, fluid-bed drying, and lyophilization were applied for granulation liquid removal. The impact of these drying techniques on the final pellet properties was evaluated. The in vitro dissolution behavior was dramatically altered by the drying techniques that were considered. The investigated pellets showed drug release rates that varied as much as 100%. As no polymorphic transitions occurred during drying, we focused on two possible explanations: (a) a change in the drug distribution within the pellets and (b) a change in pellet micro-structure (porosity, pore size). The ibuprofen distribution proved to be homogeneous regardless of the drying conditions. Pellet porosity and pore sizes, however, were modified by the drying process. Our results clearly demonstrate that a single process step, such as drying, can play a crucial role in achieving desired pellet properties and release profiles.     

Effect of Dosage Form Properties on Therapeutic Efficacy of Tolbutamide Tablets

The rate of gastrointestinal absorption and the physiologic availability of tolbutamide are functions of the dissolution rate of the drug in gastrointestinal fluids. This property can be modified markedly by pharmaceutical formulation factors. The in vitro dissolution rates of clinically efficacious and clinically inefficacious tolbutamide tablets have been determined, and it has been found that the former dissolved considerably more rapidly than the latter. Once diabetic patients have been “titrated” with a particular brand of tolbutamide they should not be switched to a different brand without “retitration.” There is need to establish an adequate in vitro test to assure the physiologic availability of tolbutamide from commercial tablets.     

Physicochemical Characterization of Berberine Chloride: A Perspective in the Development of a Solution Dosage Form for Oral Delivery

The objective of the present research was to evaluate the physicochemical characteristics of berberine chloride and to assess the complexation of drug with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a first step towards solution dosage form development. The parameters such as log P value were determined experimentally and compared with predicted values. The pH-dependent aqueous solubility and stability were investigated following standard protocols at 25°C and 37°C. Drug solubility enhancement was attempted utilizing both surfactants and cyclodextrins (CDs), and the drug/CD complexation was studied employing various techniques such as differential scanning calorimetry, Fourier transform infrared, nuclear magnetic resonance, and scanning electron microscopy. The experimental log P value suggested that the compound is fairly hydrophilic. Berberine chloride was found to be very stable up to 6 months at all pH and temperature conditions tested. Aqueous solubility of the drug was temperature dependent and exhibited highest solubility of 4.05 ± 0.09 mM in phosphate buffer (pH 7.0) at 25°C, demonstrating the effect of buffer salts on drug solubility. Decreased drug solubility was observed with increasing concentrations of ionic surfactants such as sodium lauryl sulfate and cetyl trimethyl ammonium bromide. Phase solubility studies demonstrated the formation of berberine chloride–HPβCD inclusion complex with 1:1 stoichiometry, and the aqueous solubility of the drug improved almost 4.5-fold in the presence of 20% HPβCD. The complexation efficiency values indicated that the drug has at least threefold greater affinity for hydroxypropyl-β-CD compared to randomly methylated-β-CD. The characterization techniques confirmed inclusion complex formation between berberine chloride and HPβCD and demonstrated the feasibility of developing an oral solution dosage form of the drug.KEY WORDS: berberine chloride, complexation, cyclodextrin, solubility, surfactants     

Influence of Postprandial Intragastric Pressures on Drug Release from Gastroretentive Dosage Forms

Despite extensive research in the field of gastroretentive dosage forms, this “holy grail” of oral drug delivery yet remained an unmet goal. Especially under fasting conditions, the reproducible retention of dosage forms in the stomach seems to be an impossible task. This is why such systems are often advised to be taken together with food. But also the postprandial motility can contribute significantly to the failure of gastroretentive dosage forms. To investigate the influence of postprandial pressure conditions on drug release from such systems, we used a novel in vitro dissolution tool, the dissolution stress test device. With the aid of this device, we simulated three different intragastric pressure profiles that may occur after postprandial intake. These transit scenarios were based on recently obtained, postprandial SmartPill® data. The tested systems, Glumetza® 1000 and Madopar® HBS 125, are marketed dosage forms that are based on different approaches to achieve proper gastric retention. All three transit scenarios revealed a highly pressure-sensitive drug release behavior, for both drugs. For Madopar® HBS 125, nearly complete drug release was observed even after early occurring pressures. Glumetza® 1000 seemed to be more resistant to these, most likely due to incomplete wetting of the system. On the contrary to these findings, data from standard dissolution tests using the paddle apparatus displayed controlled drug release for both systems for about 6 h. Based on these results, it can be doubted that established gastroretentive systems stay intact over a longer period of time, even under postprandial conditions.     

Power of the Dissolution Test in Distinguishing a Change in Dosage Form Critical Quality Attributes

For a dissolution method to be considered relevant to in vivo performance, the dissolution data profiles should show discrimination or meaningful change when there is a change in critical material attributes (CMAs) and critical product properties (CPPs). The dissolution test has been shown repeatedly to have the power to distinguish between significant changes in active pharmaceutical ingredient (API), formulation, and process that relate to the release mechanism of the in vivo performance. Examples will be discussed in the literature where the effects of formulation, drug substance, and manufacturing variables have been measured by dissolution testing. There will be a suggested plan on how to develop and challenge a discriminating method that may be utilized for regulatory purposes. A brief review of other challenges and considerations regarding discriminatory dissolution testing is presented.     

Ratio Spectra Derivative and Zero-Crossing Difference Spectrophotometric Determination of Olmesartan Medoxomil and Hydrochlorothiazide in Combined Pharmaceutical Dosage Form

Two simple, economical, rapid, precise, and accurate methods for simultaneous determination of olmesartan medoxomil and hydrochlorothiazide in combined tablet dosage form have been developed. The first method is based on ratio spectra derivative spectrophotometry, and the second method is zero-crossing difference spectrophotometry. The amplitudes in the first derivative of the corresponding ratio spectra at 231.0 and 271.0 nm were selected to determine olmesartan medoxomil and hydrochlorothiazide, respectively. Measurements of absorbance were carried out at zero-crossing wavelengths 257.8 and 240.2 nm for olmesartan medoxomil and hydrochlorothiazide by zero-crossing difference spectrophotometric method. Beer’s law is obeyed in the concentration range of 08–24 μg/mL for olmesartan medoxomil (OLM) and 05–15 μg/mL for hydrochlorothiazide (HCT) by ratio spectra derivative and 05–30 μg/mL for OLM and HCT by zero-crossing difference spectrophotometric method. The results of the assay were found to be 100.46 ± 0.95 for OLM and 100.4 ± 0.27 for HCT by ratio spectra derivative and 99.06 ± 1.14 for OLM and 100.05 ± 0.90 for HCT by zero-crossing difference spectrophotometric method. These methods passes F test and t test. Both methods were validated statistically and by performing recovery study.     

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

Enhancing and sustaining AMG 009 dissolution from a matrix tablet via microenvironmental pH modulation and supersaturation, where poorly soluble acidic AMG 009 molecule was intimately mixed and compressed together with a basic pH modifier (e.g., sodium carbonate) and nucleation inhibitor hydroxypropyl methylcellulose K100 LV (HPMC K100 LV), was demonstrated previously. However, not all acidic or basic drugs are compatible with basic or acidic pH modifiers either chemically or physically. The objective of this study is to investigate whether similar dissolution enhancement of AMG 009 can be achieved from a bilayer dosage form, where AMG 009 and sodium carbonate are placed in a separate layer with or without the addition of HPMC K100 LV in each layer. Study results indicate that HPMC K100 LV-containing bilayer dosage forms gained similar dissolution enhancement as matrix dosage forms did. Bilayer dosage forms without HPMC K100 LV benefitted the least from dissolution enhancement.     

Multi-scale Predictions of Drug Resistance Epidemiology Identify Design Principles for Rational Drug Design

1. Download : Download high-res image (202KB)
2. Download : Download full-size image

     

Topical Cream-Based Dosage Forms of the Macrocyclic Drug Delivery Vehicle Cucurbit[6]uril

The macrocycle family of molecules called cucurbit[n]urils are potential drug delivery vehicles as they are able to form host-guest complexes with many different classes of drugs. This study aimed to examine the utility of Cucurbit[6]uril (CB[6]) in topical cream-based formulations for either localised treatment or for transdermal delivery. Cucurbit[6]uril was formulated into both buffered cream aqueous- and oily cream-based dosage forms. The solid state interaction of CB[6] with other excipients was studied by differential scanning calorimetry and the macrocycle''s transdermal permeability was determined using rat skin. Significant solid state interactions were observed between CB[6] and the other dosage form excipients. At concentrations up to 32% w/w the buffered aqueous cream maintained its normal consistency and could be effectively applied to skin, but the oily cream was too stiff and is not suitable as a dosage form. Cucurbit[6]uril does not permeate through skin; as such, the results imply that cucurbituril-based topical creams may potentially only have applications for localised skin treatment and not for transdermal drug delivery.     

Preformulation Considerations for Controlled Release Dosage Forms: Part III. Candidate Form Selection Using Numerical Weighting and Scoring

Two numerical methods, Decision Analysis (DA) and Potential Problem Analysis (PPA) are presented as alternative selection methods to the logical method presented in Part I. In DA properties are weighted and outcomes are scored. The weighted scores for each candidate are totaled and final selection is based on the totals. Higher scores indicate better candidates. In PPA potential problems are assigned a seriousness factor and test outcomes are used to define the probability of occurrence. The seriousness-probability products are totaled and forms with minimal scores are preferred. DA and PPA have never been compared to the logical-elimination method. Additional data were available for two forms of McN-5707 to provide complete preformulation data for five candidate forms. Weight and seriousness factors (independent variables) were obtained from a survey of experienced formulators. Scores and probabilities (dependent variables) were provided independently by Preformulation. The rankings of the five candidate forms, best to worst, were similar for all three methods. These results validate the applicability of DA and PPA for candidate form selection. DA and PPA are particularly applicable in cases where there are many candidate forms and where each form has some degree of unfavorable properties. Presented at the 41st Annual Pharmaceutical Technologies Arden Conference—Oral Controlled Release Development and Technology, January 2006, West Point NY.     

特殊制剂一致性评价的开发策略

2016 年 3 月 5 日,国务院办公厅《开展仿制药质量和疗效一致性评价的意见》正式对外公布,提出了全面提高仿制药质量,开 展仿制药质量一致性评价,确保中国仿制药质量不低于美国、欧盟、日本的标准。文章介绍了美国和日本的一致性评价背景,根据中国国情, 结合政策法规,阐述如何科学性、合理性地开展仿制药一致性评价,重点介绍低剂量和微丸压片特殊口服固体制剂一致性评价的开发策略。     

抗体药物的发展与应用

早期抗体药物是鼠源单克隆抗体,存在免疫原性强、半衰期短等问题。历经数十年的发展,抗体药物从最初的鼠源单抗,逐步发展为人鼠嵌合抗体、人源化抗体及全人源化抗体。通过片段重组、位点修饰、药物偶联等方法,科研人员研发了包括抗体融合蛋白、抗体偶联药物、双特异性抗体、小分子抗体片段等形式多样的抗体药物。抗体药物在恶性肿瘤、自身免疫病、感染性疾病的治疗上发挥重要作用。通过对抗体药物人源化历程,不同类型的抗体结构和特点,以及抗体药物在新型冠状病毒肺炎治疗中的应用进行综述,并对抗体药物的发展前景进行展望,以期为我国抗体药物的研发提供参考。