Engineering Active Pharmaceutical Ingredients by Spray Drying: Effects on Physical Properties and In Vitro Dissolution

Active pharmaceutical ingredients have very strict quality requirements; minor changes in the physical and chemical properties of pharmaceuticals can adversely affect the dissolution rate and therefore the bioavailability of a given drug. Accordingly, the aim of the present study was to investigate the effect of spray drying on the physical and in vitro dissolution properties of four different active pharmaceutical ingredients, namely carbamazepine, indomethacin, piroxicam, and nifedipine. Each drug was dispersed in a solution of ethanol and water (70:30) and subjected to single-step spray drying using similar operational conditions. A complete characterization of the spray-dried drugs was performed via differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), particle size distribution analysis, solubility analysis, and an in vitro dissolution study. The results from the thermal analysis and X-ray diffraction showed that, except for carbamazepine, no chemical modifications occurred as a result of spray drying. Moreover, the particle size distribution of all the spray-dried drugs significantly decreased. In addition, SEM images showed that most of the particles had an irregular shape. There was no significant improvement in the solubility of the spray-dried drugs compared with the unprocessed compounds; however, in general, the dissolution rates of the spray-dried drugs showed a remarkable improvement over their non-spray-dried counterparts. Therefore, the results from this study demonstrate that a single spray-drying step may lead to changes in the physical properties and dissolution characteristics of drugs and thus improve their therapeutic action.

Silk Fibroin: a biopolymer platform for innovative pharmaceutical formulation and biomedical devices.

The protein silk fibroin (SF) from the silkworm Bombyx mori is a FDA-approved biomaterial used over centuries as sutures wire. Importantly, several evidences highlighted the potential of silk biomaterials obtained by using so-called regenerated silk fibroin (RSF) in biomedicine, tissue engineering and drug delivery. Indeed, by a water-based protocol, it is possible to obtain protein water-solution, by extraction and purification of fibroin from silk fibres. Notably, RSF can be processed in a variety of biomaterials forms used in biomedical and technological fields, displaying remarkable properties such as biocompatibility, controllable biodegradability, optical transparency, mechanical robustness. Moreover, RSF biomaterials can be doped and/or chemical functionalized with drugs, optically active molecules, growth factors and/or chemicals In this view, activities of my PhD research program were focused to standardize the process of extraction and purification of protein to get the best physical and chemical characteristics. The analysis of the chemo-physical properties of the fibroin involved both the RSF water-solution and the protein processed in film. Chemo-physical properties have been studied through: vibrational (FT-IR and Raman-FT) and optical (absorption and emission UV-VIS) spectroscopy, nuclear magnetic resonance (1H and 13C NMR), thermal analysis and thermo-gravimetric scan (DSC and TGA). In the last year of my PhD, activities were focused to study and define innovative methods of functionalization of the silk fibroin solution and films. Indeed, research program was the application of different methods of manufacturing approaches of the films of fibroin without the use of harsh treatments and organic solvents. New approaches to doping and chemical functionalization of the silk fibroin were studied. Two different methods have been identified: 1) biodoping that consists in the doping of fibroin with optically active molecules through the addition of fluorescent molecules in the standard diet used for the breeding of silkworms; 2) chemical functionalization via silylation.

Optimization of molecular and crystalline forms of drugs, agrochemicals, pesticides in relation to activity, bioavailability, patentability and to the fabrication of polymorphs, solvates, co-crystals with green chemistry methods

This doctorate was funded by the Regione Emilia Romagna, within a Spinner PhD project coordinated by the University of Parma, and involving the universities of Bologna, Ferrara and Modena. The aim of the project was: - Production of polymorphs, solvates, hydrates and co-crystals of active pharmaceutical ingredients (APIs) and agrochemicals with green chemistry methods; - Optimization of molecular and crystalline forms of APIs and pesticides in relation to activity, bioavailability and patentability. In the last decades, a growing interest in the solid-state properties of drugs in addition to their solution chemistry has blossomed. The achievement of the desired and/or the more stable polymorph during the production process can be a challenge for the industry. The study of crystalline forms could be a valuable step to produce new polymorphs and/or co-crystals with better physical-chemical properties such as solubility, permeability, thermal stability, habit, bulk density, compressibility, friability, hygroscopicity and dissolution rate in order to have potential industrial applications. Selected APIs (active pharmaceutical ingredients) were studied and their relationship between crystal structure and properties investigated, both in the solid state and in solution. Polymorph screening and synthesis of solvates and molecular/ionic co-crystals were performed according to green chemistry principles. Part of this project was developed in collaboration with chemical/pharmaceutical companies such as BASF (Germany) and UCB (Belgium). We focused on on the optimization of conditions and parameters of crystallization processes (additives, concentration, temperature), and on the synthesis and characterization of ionic co-crystals. Moreover, during a four-months research period in the laboratories of Professor Nair Rodriguez-Hormedo (University of Michigan), the stability in aqueous solution at the equilibrium of ionic co-crystals (ICCs) of the API piracetam was investigated, to understand the relationship between their solid-state and solution properties, in view of future design of new crystalline drugs with predefined solid and solution properties.

Nanoparticular iron complex drugs for parenteral administration - physicochemical characterization, biological distribution and pharmacological safety

Iron deficiency is the most common deficiency disease worldwide with many patients who require intravenous iron. Within the last years new kind of parenteral iron complexes as well as generic preparations entered the market. There is a high demand for methods clarifying benefit to risk profiles of old and new iron complexes. It is also necessary to disclose interchangeability between originator and intended copies to avoid severe anaphylactic and anaphylactoid side reaction and assure equivalence of therapeutic effect.rnrnThe investigations presented in this work include physicochemical characterization of nine different parenteral iron containing non-biological complex drugs. rnWe developed an in-vitro assay, which allows the quantification of labile iron in the different complexes and thus it is a useful tool to estimate the pharmaclogical safety regarding iron related adverse drug events. This assay additionally allowed the estimation of complex stability by evaluation of degradation kinetics at the applied conditions.rnrnAn in-ovo study was performed to additionally compare different complexes in respect to body distribution. This in combination with complex stability information allowed the risk estimation of potential local acute and chronic reactions to iron overload.rnrnInformation obtained by the combination of the methods within this work are helpful to estimate the safety and efficacy profile of different iron containing non-biological complex drugs. rnrnPhysicochemical differences between the complexes were demonstrated in respect to size of the inorganic fraction, size and size distribution of the complete particles, structure of the inorganic iron fraction, morphology of the complexes and charge of the complexes. And furthermore significant differences in the biological behavior of different complexes were demonstrated. rnrnThe combination of complex stability and biodistribution as well as the combination of structure, size and stability represent helpful tools for the physicochemical characterization of iron containing non-biological complex drugs and for the estimation of pharmacological safety. This work thus represents an up to date summary of some relevant methods for the characterization of intravenous iron complex drugs in respect to pharmaceutical quality, pharmacological safety and aspects of efficacy. rnrnProspectively, it is worthwhile that the methods within this work will contribute to the development and/or characterization of iron containing nanoparticular formulations with beneficial efficacy and safety profiles.rn

State Pharmaceutical Assisstance for the Elderly and Disabled: Planning Issues for Program and Non-Program States

The Medicare Catastrophic Coverage Act (MCCA) would have mandated federal assistance for Medicare beneficiaries who have high annual prescription medication costs, High national expenditures for such drugs have encouraged the development of private and state insurance programs to help with these costs. Ten state pharmaceutical assistance programs (SPAPs), designed to help certain elderly, low income, or disabled people, exist for those ineligible for Medicaid or unable to purchase coverage privately. Coordination of state and federal benefits was a consideration for established programs, and programs being planned needed to determine the feasibity of integration of federal assistance. But the enactment and subsequent appeal of the Act affected both planning and policy implications for these SPAPs. All U.S. states and territories were surveyed before the bill's repeal to collect data on the effects of MCCA for those with prescription drug programs and those without. The repeal of the federal program places pressure on the nonprogram states to proceed, perhaps more cautiously, to initiate program; for their own residents, given increasing out-of-pocket and insurance costs, and no federal program.

Noncovalent interactions of drugs with immune receptors may mediate drug-induced hypersensitivity reactions

Drug-induced hypersensitivity reactions are instructive examples of immune reactions against low molecular weight compounds. Classically, such reactions have been explained by the hapten concept, according to which the small antigen covalently modifies an endogenous protein; recent studies show strong associations of several HLA molecules with hypersensitivity. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the major histocompatibility complex (MHC)-peptide complex in order to trigger an immune response. Rather, some drugs may bind reversibly to the MHC or possibly to the T-cell receptor (TCR), eliciting immune reactions akin to the pharmacological activation of other receptors. While the exact mechanism is still a matter of debate, noncovalent drug presentation clearly leads to the activation of drug-specific T cells. In some patients with hypersensitivity, such a response may occur within hours of even the first exposure to the drug. Thus, the reaction to the drug may not be the result of a classical, primary response but rather be mediated by existing, preactivated T cells that display cross-reactivity for the drug and have additional (peptide) specificity as well. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the idiosyncratic nature of many drug hypersensitivity reactions.

Orphan drugs and paediatric medicinal products

While the safety and availability of medicinal products for the majority of adult patients has steadily improved in recent decades, for children and people suffering from rare diseases (orphan diseases) there is a lack of approved medicinal products for these patient populations. Since the research and development of medicinal products is associated with high costs, the costs for paediatric medicinal products and medicines for rare diseases (orphan drugs) may barely be covered under normal market conditions due to the small patient populations. In order to prevent the continued exclusion of children and persons suffering from rare diseases from medical progress and to eliminate the deficits in the research and development of medicinal products for these patient groups, the European Union created, along the lines of the U.S. model, a system of incentives and constraints. Since 2000, under Regulation (EC) No. 141/2000 (Orphan Drug Regulation) there has been an incentive system to encourage the research and development of orphan drugs. With the goal of improving the health of children in Europe, Regulation (EC) No. 1901/2006 (Paediatric Regulation) combines economic incentives with the requirement to conduct paediatric studies. This article explains and comments on the specific regulatory framework for orphan drugs and paediatric medicinal products in the European Union.

Inferring the Effects of Vertical Integration from Entry Games : An Analysis of the Generic Pharmaceutical Industry

This paper introduces a novel method for examining the effects of vertical integration. The basic idea is to estimate the parameters of a vertical entry game. By carefully specifying firms' payoff equations and constructing appropriate tests, it is possible to use estimates on rival profit effects to make inferences about the existence of vertical foreclosure. I estimate the vertical entry model using data from the US generic pharmaceutical industry. The estimates indicate that vertical integration is unlikely to generate anticompetitive foreclosure effects. On the other hand, significant efficiency effects are found to arise from vertical integration. I use the parameter estimates to simulate a policy that bans vertically integrated entry. The simulation results suggest that such a ban is counterproductive; it is likely to reduce entry into smaller markets.

Quality of pharmaceutical advertising and gender bias in medical journals (1998-2008): a review of the scientific literature

Objective: To review the scientific literature on pharmaceutical advertising aimed at health professionals in order to determine whether gender bias has decreased and the quality of information in pharmaceutical advertising has improved over time. Methods: We performed a content analysis of original articles dealing with medical drug promotion (1998-2008), according to quality criteria such as (a) the number, validity and accessibility of bibliographic references provided in pharmaceutical advertising and (b) the extent to which gender representations were consistent with the prevalence of the diseases. Databases: PUBMED, Medline, Scopus, Sociological Abstract, Eric and LILACS. Results: We reviewed 31 articles that analyzed advertising in medical journals from 1975-2005 and were published between 1998 and 2008. We found that the number of references used to support pharmaceutical advertising claims increased from 1975 but that 50% of these references were not valid. There was a tendency to depict men in paid productive roles, while women appeared inside the home or in non-occupational social contexts. Advertisements for psychotropic and cardiovascular drugs overrepresented women and men respectively. Conclusions: The use of bibliographic references increased between 1998 and 2008. However, representation of traditional male-female roles was similar in 1975 and 2005. Pharmaceutical advertisements may contribute to reinforcing the perception that certain diseases are associated with the most frequently portrayed sex.

Outpatient prescription drugs : data collection and editing in the 1996 Medical Expenditure Panel Survey (HC-010A).

"June 2001."

Medicinal chemistry : chemistry, biochemistry, therapeutic and pharmacological action of natural and synthetic drugs.

Errata slip inserted in v. 1.

Administered prices: drugs. : Report of the Committee on the Judiciary, United States Senate, made by its Subcommittee on Antitrust and Monopoly, pursuant to S. Res. 52, Eighty-seventh Congress, first session, together with individual views to study the Antitrust laws of the United States, and their administration, interpretation, and effect /

Mode of access: Internet.

Patent term extension and pharmaceutical innovation [microform] : hearing before the Subcommittee on Investigations and Oversight of the Committee on Science and Technology, U.S. House of Representatives, Ninety-seventh Congress, second session, February 4, 1982.

"No. 155."

The Edinburgh new dispensatory ... : digested in a regular method and the different departments : enriched by the Introduction and application of the later discoveries in Natural History, Chemistry, and Medicines ... new tables of elective atractions ... and copperplates of chemical and pharmaceutical instruments ... / by gentlemen of the Faculty at Edinburgh

Mode of access: Internet.

Drugs--current good manufacturing practice in manufacture, processing, packing, or holding. : regulations under the Federal Food, Drug, and Cosmetic Act, Part 133, Title 21, Code of Federal Regulations. Part 191, Hazardous substances.

Mode of access: Internet.