Drug Product Formulation Research Articles

Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products.

Here, we describe a protocol developed by our group that uses low-field fluorine-19 (19F) time-domain (TD) nuclear magnetic resonance (NMR) to measure the average content of fluorinated drugs in their formulated drug product forms: tablets or capsules. This method is specific to fluorinated drugs because it detects only the content of fluorine, avoiding interference from the excipients that lack fluorine. The advantages of measuring the active content of fluorinated drugs using low-field 19F TD-NMR versus high-field 19F solid-state (SS) NMR are the simplicity of the method; the low cost; and the non-destructive nature of the technique, with all samples recoverable in intact forms (e.g., powders, tablets, and capsules), making this technique affordable for any laboratory. We have tested the method with three fluorinated drug products available on the market - cinacalcet, lansoprazole, and ciprofloxacin - with doses ranging from 15 to 500 mg. The results of the analyses, measured by low-field 19F TD-NMR, supported the reported label claims for the average drug content. Based on the simplicity and reproducibility of the analysis, we envision this methodology being implemented in any laboratory, including manufacturing plants, as a process analytical technology (PAT) tool in the pharmaceutical industry.

Role of regional absorption and gastrointestinal motility on variability in oral absorption of a model drug

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.

İlaç Formülasyonu Geliştirilmesinde Deney Tasarımı (DoE) Seçimi ve Kullanımı

In recent years, despite of the increasing use of design of experiments (DoE) in the development of drug product formulation, it has still not been sufficient. It has been known that using DoE is very useful particularly formulation of solid and semi-solid dosage forms including many components and many process parameters with unknown effect on outputs. Proper use and selection of the DoE is also important at least as using DoE in the development of drug product formulation instead of the old approaches such as trial and error. Non-correctly selected type of DoE or inappropriately applied experiments and measurements results not only wasted resources and time, but also often produces confusing or misleading data. In this review, summary information about DoE, selection of suitable type of DoE, reduction of the number of factors by using statistical screening and optimization of the drug formulations using response surface modeling (RSM) are intended to give, also briefly mentioned about the application of these methods in the development of pharmaceutical formulation. A lot of quality information (mathematical models) can be produced from the few trials conducted by means of selecting and implementation of the correct type of DoE. Thus, the development time and cost can be reduced significantly. Developed product may also have a robust process which is not sensitive to variations.

Formulation and in vitro Evaluation of In-situ Gelling Liquid Suppositories for Naproxen

In-situ gelation is a process of gel formation at the site of application, in which a drug product formulation that exists as a liquid has been transformed into a gel upon contact with body fluids. As a drug delivery agent, the in-situ gel has an advantage of providing sustained release of the drug agent. In-situ gelling liquid suppositories using poloxamer 188 (26-30% W/W) as a suppository base with 10% W/W naproxen were prepared, the gelation temperature of these preparations were measured and they were all above the physiological temperature. Additives such as polyvinylpyrrolidin "PVP" ,hydroxylpropylmethylcellulose "HPMC", sodium alginate and sodium chloride were used in concentration ranging from (0.25-1%W/W) to modulate the gelation temperature and gel strength .The best preparation was obtained through using a combination of poloxamer 188, sodium alginate, naproxen and distilled water (29,0.5,10and 60.5 % W/W respectively)with gelation temperature of 33.6ºC±0.2 and gel strength of 28±2 seconds. The release of drug from this preparation was sustained for about 12 hours and it was faster than conventional solid suppository (Proxen® 500) and oral tablets (Naproxen®500) using dialysis tubing method.
 Key words: - naproxen, in-situ gelation, liquid suppository, poloxamer188

Data-Driven Design of an Ebola Therapeutic

Formulation is very important in drug delivery. The wrong formulation can render a drug product useless. The amount of preclinical (animal and in vitro) work that must be done before a new drug candidate can be tested in humans can be a problem. The cost of these cGxP studies is typically $3-$5 million. If the wrong drug product formulation is tested, new iterations of the formulation must be tested with additional costs.Data-driven computational science can help reduce this cost. In the absence of existing human exposure, a battery of preclinical tests must be performed in at least two species before FDA will permit testing in humans. However, for many drugs (such as those beginning with natural products) there is a history of human exposure. In these cases, computer modeling of a population to determine human exposure may be adequate to permit phase 1 studies with a candidate formulation in humans.The CDC’s National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews and physical examinations including laboratory results. The NHANES database can be mined to determine exposure to a food additive, and early human formulation testing conducted at levels beneath those to which the US population is ordinarily exposed through food. These data can be combined with data mined from international chemical shipments to validate an exposure model. This paper describes the data driven formulation testing process using a new candidate Ebola treatment that, unlike vaccines, can be used after a person has contracted the disease. This drug candidate’s mechanism of action permits it to be potentially used against all strains of the virus, a characteristic that vaccines might not share.

Enhanced Delivery of DNA or RNA Vaccines by Electroporation.

Nucleic acid vaccines are a next-generation branch of vaccines which offer major benefits over their conventional protein, bacteria, or viral-based counterparts. However, to be effective in large mammals and humans, an enhancing delivery technology is required. Electroporation is a physical technique which results in improved delivery of large molecules through the cell membrane. In the case of plasmid DNA and mRNA, electroporation enhances both the uptake and expression of the delivered nucleic acids. The muscle is an attractive tissue for nucleic acid vaccination in a clinical setting due to the accessibility and abundance of the target tissue. Historical clinical studies of electroporation in the muscle have demonstrated the procedure to be generally well tolerated in patients. Previous studies have determined that optimized electroporation parameters (such as electrical field intensity, pulse length, pulse width and drug product formulation) majorly impact the efficiency of nucleic acid delivery. We provide an overview of DNA/RNA vaccination in the muscle of mice. Our results suggest that the technique is safe and effective and is highly applicable to a research setting as well as scalable to larger animals and humans.

Mechanistic approach in powder blending PAT: Bi-layer mixing and asymptotic end point prediction

We derive a simple first order kinetics model for the powder mixing in a bin blender and adapt it to fit the NIR spectra obtained during the real-time mixing. The model is tested on a full drug product formulation mixing consisting of API and multiple excipients. It allows to extract a quantitative mixing rate for individual ingredients, which may be used in the drug development and production scale-up design. We further propose an algorithm for a calibration-free blending end-point determination from the NIR data, which allows for a robust and easily transferable blending process control.

Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.

Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the quality by design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.

Utility of Solution X-Ray Scattering for the Development of Antibody Biopharmaceuticals

Characterization of immunoglobulin solutions at high concentrations represents a significant challenge. A current trend in the biopharmaceutical industry is to manufacture highly concentrated drug products, which can be used to deliver high doses in small volumes, via subcutaneous injections. Studying a molecule's structure and properties in its final drug product formulation is ideal, but characterization is typically performed under dilute solution conditions with critical stabilizing buffer components removed because of interference effects, which can result in an incomplete understanding of the molecule's properties. Direct study of protein conformation and protein-protein interactions in concentrated solutions is challenging for most biophysical and biochemical techniques; however, X-ray solution scattering offers opportunities. Combined with other biophysical techniques, X-ray scattering has the potential to provide relevant information on both structure and interactions in protein solutions over a broad concentration range. Here, we report X-ray solution scattering of 4 monoclonal antibodies, designated mAb1 (glycosylated and de-glycosylated), mAb2, and mAb3 at concentrations between 0.5 and >168 mg/mL. Data acquired from these measurements are combined with the results from other biophysical measurements to generate a comprehensive profile of their solution behaviors. Our results show that X-ray solution scattering can assess key parameters needed to aid in formulation development.

Cell culture media impact on drug product solution stability.

To enable subcutaneous administration of monoclonal antibodies, drug product solutions are often needed at high concentrations. A significant risk associated with high drug product concentrations is an increase in aggregate level over the shelf-life dating period. While much work has been done to understand the impact of drug product formulation on aggregation, there is limited understanding of the link between cell culture process conditions and soluble aggregate growth in drug product. During cell culture process development, soluble aggregates are often measured at harvest using cell-free material purified by Protein A chromatography. In the work reported here, cell culture media components were evaluated with respect to their impact on aggregate levels in high concentration solution drug product during accelerated stability studies. Two components, cysteine and ferric ammonium citrate, were found to impact aggregate growth rates in our current media (version 1) leading to the development of new chemically defined media and concentrated feed formulations. The new version of media and associated concentrated feeds (version 2) were evaluated across four cell lines producing recombinant IgG4 monoclonal antibodies and a bispecific antibody. In all four cell lines, the version 2 media reduced aggregate growth over the course of a 12 week accelerated stability study compared with the version 1 media, although the degree to which aggregate growth decreased was cell line dependent. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:998-1008, 2016.

Chemotherapeutic effect of 3, 3′-Diindolylmethane encapsulated chitosan nanoparticles on 7, 12-Dimethylbenz (a) anthracene induced mammary cancer – A dose dependent study

Breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetic factors are believed to account for only 10% of the reported cases, remaining the environmental factors, including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds have been reported for their anticancer potential. One among the bioactive compound 3, 3′-Diindolylmethane (DIM) is a phytochemical possess a wide array of pharmacological activities such as anti-proliferative and anti-oxidant properties. Its properties such as poor water solubility and low bioavailability have hampered its clinical development.Therefore, it is a great interest to study whether the nano formulation for DIM with chitosan for its enhanced potential, the present study was aimed to evaluate the chemotherapeutic potential of 3, 3′- Diindolylmethane encapsulated chitosan nanoparticles (DIM@CS-NP) on 7,12-Dimethylbenz(a)anthracene (DMBA) induced mammary carcinoma in rats. DMBA was induced in a single subcutaneous injection of 25mg/ kg body weight to each rat. In the present study, we investigated the altered activities of lipid peroxidation, enzymatic antioxidants (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in plasma, liver and mammary tissue, supported by histopathological study of mammary tissues. We evaluated the changes in the body weight of control and experimental animals. There was a significant decrease in the final body weight of tumor bearing animals, when compared to control animals. Also, we observed a diminished cellular antioxidant status and the elevated oxidant levels in plasma, liver, mammary tissues of DMBA induced rats. However, administration of DIM@CS-NP significantly increased the mean final body weight when compared with DMBA induced animals. Oral supplementation of different doses of DIM@CS-NP (0.5, 1, 2 mg/kg BW), significantly renovated the activities of cellular antioxidants and ultimately diminished the levels of lipid peroxidation, which pointed towards suppression of preneoplastic lesions, thereby reduced the cancer risk, and significant improvement in the levels of enzymatic (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in the plasma, liver and mammary tissue. Based on the above finding we conclude the nano formulation of DIM provides a novel therapeutic regime for mammary cancer.Focal points:•Benchside○Oxidants, antioxidant status and histopathological examination of mammary tumor tissue are necessary to determine the chemotherapeutic potential of DIM@CS-NP on experimental induced rat mammary carcinoma.•Bedside○Ingestion of DIM@CS-NP may reduce the severity of DMBA induced tumor bearing animals. More over nanoformulated drug delivery systems from biocompatible and biodegradable polymers contributes an evolving approach in drug delivery and tumor targeting.•Industry○New formulated compounds from cruciferous vegetables consider one of the best chemotherapeutic potential for various malignancies.•Community○The development of nano formulated products with chemotherapeutic potential by pharmaceutical industry could provide local economic benefits as well as patient convenience.•Regulatory agencies○Nano formulated drug products produced from the cruciferous vegetables for better improvement in drug delivery and sustained drug release system are certain advantages compared to conventional form of drug dosages, as they can minimize side effects, and also prolong the efficacy of the drug. This will need to be taken for labelling and pattering the nanoformulated compounds and tested in clinical trials.

Amorphous solid dispersions of BCS class II drugs: A rational approach to solvent and polymer selection

Miniaturised solvent casting (MSC) has been developed as a method for screening the stability of amorphous solid dispersions (ASD) of BCS class II drugs. The aim of the work was to further develop a rapid screening technique for drug–polymer amorphous dispersions made by solvent removal techniques. A second aim was to assess the impact of varying dissolution solvent on the resultant ASD stability. The technique was rapid, repeatable and practically straightforward. Storage stability of resultant ASD films was monitored over 4 weeks. The method is suited to pre-formulation as a risk-reduction tool during the formulation of drug product. Four drugs, seven polymers and five solvents have been examined. The resultant ASD films were monitored for stability and homogeneity over a four week period using polarised light microscopy (PLM), X-ray powder diffraction (XRD) and photography. A qualitative scoring system indicating the approximate proportion of amorphous and crystalline content of the films was developed. Results were rationalised against the physiochemical properties of the drugs, the functionality of the polymeric excipients and the physical properties of the solvents.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison

The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5mg testosterone and 50mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme. Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil. Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06ngml(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69ngml(-1) h (95% CI 6.22, 9.16) than formulation 1, 5.66ngml(-1) (95% CI 4.63, 6.69) and 5.12ngml(-1) h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173ngml(-1) (95% CI 126, 220) and a lower AUC, 476ngml(-1) h (95% CI 401, 551) than formulation 1, 268ngml(-1) (95% CI 188, 348) and 577ngml(-1) h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75h (95% CI 2.40, 3.10). The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues. A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies.

Formulation factors affecting the isomerization rate of betamethasone-17-valerate in a developmental hydrophilic cream – a HPLC and microscopy based stability study

The formulation of betamethasone-17-valerate (BV) into topical medicines presents a significant challenge for the formulation chemist. The substance is susceptible to acid and base catalyzed isomerization in aqueous environments, which results in valerate transesterification from carbon 17 to carbon 21 of the steroid ring system. This acyl migration process is of significant clinical importance since the 21-valerate ester possesses only a fraction of the potency of the 17-valerate parent compound. Isomerization of BV should therefore be reduced to a minimum through design of a suitable drug vehicle. In this study, the effect of varying the concentration of several excipient components on the isomerization rate of betamethasone valerate in a model hydrophilic cream has been investigated. These excipients include the emulsifier macrogolstearylether-20/21, the co-emulsifier cetylstearyl alcohol and the thickening agent hydroxyl propyl methylcellulose. Additionally, the influence of pH, the presence of the antioxidant, alpha-tocopherol, as well as the chelating agent, disodium edetate, on the stability of the formulation have been investigated. Trial drug product formulations, which were designed to investigate the influence of the above-mentioned components/parameters were manufactured and their stability was tested according to current ICH Guidelines. The content, purity and crystalline structure of the active substance in these formulations was analyzed by a combination of HPLC and microscopy techniques. The study demonstrates that the rate of isomerization of betamethasone valerate depends significantly on the concentration of emulsifier used in the cream formulation. At higher concentrations of emulsifier the isomerization proceeds rapidly with significant degradation over a period of weeks, whereas at lower concentrations significant degradation may not be observed, even after several years’ storage. The influence of the emulsifier has been shown to be independent of the pH value of the aqueous phase of the cream. These findings have not been reported in previous literature reports on this topic, which have tended to focus on the influence of pH. The results are likely to be of interest to pharmaceutical chemists working on the formulation of glucocorticoids as well as to local- and hospital pharmacists who carry out the practice of dilution of proprietary corticoid preparations, where the choice of diluent is likely to be critical for ensuring the stability of the diluted product.

P-B32 cGMP production, characterization, and formulation of IHV01 drug product, the Full Length Single Chain gp120- CD4 (FLSC) chimera formulated in Aluminum Phosphate

The FLSC vaccine is fusion protein consisting of a modified full length gp120 protein, derived from HIVBaL, and the first 2 domains (D1D2) of human CD4, genetically fused via a 20 amino acid linker. Experiments in Rhesus macaques demonstrated protection using HEK 293 cell produced rhesus FLSC. A master cell bank expressing human FLSC was prepared from G293H, a derivative of HEK-293 cell that grows in suspension, using the GPEx retrovector transduction system. Tumorgenicity studies performed in athymic nude mice demonstrated that the FLSC MCB generated tumors at the same rate as the HEK-293 cell line available from ATCC. Bioreactor production rates were consistent from the 2 L to the 200 L scale, yielding approximately 1 g/L after downstream purification. Drug substance was predominately monomeric, and expressed the expected CD4 induced structure. A drug product formulation with aluminum phosphate was developed. Potency studies demonstrated a significant relationship between the dose of the FLSC/Alum (IHV01) and the induction of the desired CD4i directed immune response. Immunogenicity studies performed in rhesus macaques showed that the FLSC/Alum formulation induced antibodies directed to CD4i epitopes and mediated ADCC activity while T cell responses were modest. A repeat-dose (N+1) toxicity study in rabbits demonstrated that the majority of the effects observed were attributed to general inflammation occurring with intramuscular vaccine administration and/or an active immune response towards the antigen. An immunotoxicity study in cynomolgus monkeys showed no deleterious autoimmune effects directed to CD4. A phase 1 clinical trial with IHV01 is anticipated to start in September, 2015.

Vitamin K2-4 and K2-7 Estimation in Nutraceutical Solid Dosage Forms by Post Column Derivatization with Fluorescence Detection

A post column derivatization method for the estimation of fat soluble vitamins K2-4 and K2-7 was developed by reverse phase HPLC and validated as per ICH guidelines. The compounds were extracted by solvent extraction with acetone followed by evaporation in a rotary evaporator. The residue was dissolved in ethanol and injected in to a chromatograph consists of C18 column (Waters symmetry, 150×4.6, 3.5 μ) and fluorescence detector. The derivatization reagent was prepared by dissolving 136 mg of zinc chloride, 40 mg of sodium acetate and 0.1 ml of glacial acetic acid in methanol. The mobile phase comprises of methanol: isopropyl alcohol: acetonitrile: zinc chloride buffer solution 850:90:50:10 with a flow rate of 1 ml/min. The overall percentage recovery of five different levels were found to be 99.85 and 100.5%, respectively. The linearity of the analytical method was determined from 10% to 120% level and the linear regression coefficients were 0.9991 and 0.9995 which is well within the acceptance criteria of 0.999. The limits of detection and limits of quantification was determined based on signal to noise ratio.The established values were 0.050, 0.50 μg/ml and 0.005, 0.047 μg/ml which is much lesser than available literatue limits. The developed method can be more suitable for the estimation of K2-4 and K2-7 present in drug substances as well as drug product formulations.

Integration of Regulatory Guidelines into Protein Drug Product Development.

The drug product development process for proteins went through its infancy in the early eighties of last century and is in its maturity today. This has been driven largely by the rapid growth of the biotechnology industry, which led to the development and issuance of many regulatory guidelines/directories, especially those through the International Conference of Harmonization (ICH). These guidelines have certainly guided different aspects of a drug product development process. On the other hand, they were issued separately on different topics and in different time periods. An integration of all relevant guidelines into the corresponding areas in drug product development would greatly facilitate the development process. The purpose of this short review is to integrate the relevant (mainly ICH) regulatory guidelines into protein drug product development and to discuss remaining issues, which may lead to further revision of existing guidelines or development of new ones. Drug product development scientists need to collect adequate and relevant development data for a successful product registration. The key is the ability to justify the final drug product in terms of choice of the drug product formulation, container closure system, and manufacturing process. The drug product development process for proteins has matured today, largely due to the rapid growth of the biotechnology industry. In this process, many regulatory guidelines/directories were developed and issued, especially through the International Conference of Harmonization (ICH). However, they were issued separately on different topics and in different time periods. An integration of all relevant guidelines into the corresponding areas in drug product development would greatly facilitate the development process. The purpose of this short review is to integrate the relevant (mainly ICH) regulatory guidelines into protein drug product development and to discuss remaining issues, which may lead to further revision of existing guidelines or development of new ones. Drug product development scientists need to collect adequate and relevant development data for a successful product registration. The key is the ability to justify the final drug product in terms of choice of the product formulation, container closure system, and manufacturing process.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine

Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.

Put a label (claim) on it: Getting non-surgical contraceptives approved for use in cats and dogs.

Non-surgical contraceptives or sterilants need regulatory approval to be sold for that use. This approval process gives veterinarians the information required to assess the benefits and risks of each product, and to provide comprehensive information on the required dose, method and duration of use, safety and effectiveness. This article reviews the information that must be developed and provided to regulatory agencies worldwide, with a focus on the European Union and the United States, in order to achieve regulatory approval. The main components of developing a drug include developing extensive information on the safety and effectiveness of the product, and also the safety to the environment and to humans handling and administering the drug. Most importantly, a robust method of manufacturing both the drug itself and the formulated drug product (pill, liquid implant or injection) must be developed to assure quality and consistency in each batch. This information is then compiled and submitted to regulatory agencies; in the United States, this includes the Food and Drug Administration, the United States Department of Agriculture and the Environmental Protection Agency, and, in Europe, the European Medicines Agency. Because of the unique nature of non-surgical contraceptives for use in cats and dogs, particularly the desire to have these products last over multiple years, there are special challenges to their regulatory approval that are discussed in this review.

A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components

Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations.