Recent Patents on Drug Delivery & Formulation (v.7, #1)

Preface by Mark A. Babizhayev (1-2).

The in vitro generation of hematopoietic stem cells (HSCs) and mature hematopoietic cells from hemangioblast derived from embryonic stem (ES) or induced pluripotent stem (iPS) cells promises to provide an alternative source of cells that could replace total bone marrow cells or HSC-enriched fractions. This mini-review deals with innovation related to hemangioblast-based methods for blood cells production as disclosed in recent patent literature and current barriers to clinical translation are discussed.

Biodegradable Composite Scaffolds: A Strategy to Modulate Stem Cell Behaviour by Ilaria Armentano, Elena Fortunati, Samantha Mattioli, Nicolatta Rescignano, Jose M. Kenny (9-17).
The application of new biomaterial technologies offers the potential to direct the stem cell fate, targeting the delivery of cells and reducing immune rejection, thereby supporting the development of regenerative medicine. Cells respond to their surrounding structure and with nanostructures exhibit unique proliferative and differentiation properties. This review presents the relevance, the promising perspectives and challenges of current biodegradable composite scaffolds in terms of material properties, processing technology and surface modification, focusing on significant recent patents in these fields. It has been reported how biodegradable porous composite scaffolds can be engineered with initial properties that reproduce the anisotropy, viscoelasticity, tension-compression non-linearity of different tissues by introducing specific nanostructures. Moreover the modulation of electrical, morphological, surface and topographic scaffold properties enables specific stem cell response. Recent advances in nanotechnology have allowed to engineer novel biomaterials with these complexity levels. Understanding the specific biological response triggered by various aspects of the fibrous environment is important in guiding the design and engineering of novel substrates that mimic the native cell matrix interactions in vivo.

Pluripotent stem cells hold unprecedented potential for regenerative medicine, disease modeling and drug screening. Embryonic stem cells (ESCs), standard model for pluripotency studies, have been recently flanked by induced pluripotent stem cells (iPSCs). iPSCs are obtained from somatic cells via epigenetic and transcriptional reprogramming, overcoming ESC-related ethical issues and enabling the possibility of donor-matching pluripotent cell lines. Since the European Court of Justice banned patents involving embryo disaggregation to generate human ESCs, iPSCs can now fuel the willingness of European companies to invest in treatments based on stem cells. Moreover, iPSCs share many unique features of ESCs, such as unlimited self-renewal potential and broad differentiation capability, even though iPSCs seem more susceptible to genomic instability and display epigenetic biases as compared to ESCs. Both ESCs and iPSCs have been intensely investigated for cardiomyocyte production and cardiac muscle regeneration, both in human and animal models. In vitro and in vivo studies are continuously expanding and refining this field via genetic manipulation and cell conditioning, trying to achieve standard and reproducible products, eligible for clinical and biopharmaceutical scopes. This review focuses on the recently growing body of patents, concerning technical advances in production, expansion and cardiac differentiation of ESCs and iPSCs.

In Vitro Osteogenesis of Human Stem Cells by Using a Three-Dimensional Perfusion Bioreactor Culture System: A Review by Gabriele Ceccarelli, Nora Bloise, Marco Vercellino, Rosalia Battaglia, Lucia Morgante, Maria Gabriella Cusella De Angelis, Marcello Imbriani, Livia Visai (29-38).
Tissue engineering (by culturing cells on appropriate scaffolds, and using bioreactors to drive the correct bone structure formation) is an attractive alternative to bone grafting or implantation of bone substitutes. Osteogenesis is a biological process that involves many molecular intracellular pathways organized to optimize bone modeling. The use of bioreactor systems and especially the perfusion bioreactor, provides both the technological means to reveal fundamental mechanisms of cell function in a 3D environment, and the potential to improve the quality of engineered tissues. In this mini-review all the characteristics for the production of an appropriate bone construct are analyzed: the stem cell source, scaffolds useful for the seeding of pre-osteoblastic cells and the effects of fluid flow on differentiation and proliferation of bone precursor cells. By automating and standardizing tissue manufacture in controlled closed systems, engineered tissues may reduce the gap between the process of bone formation in vitro and subsequent graft of bone substitutes in vivo.

While cataract surgery is generally recognized as being one of the safest operations, there is still a significant complication rate. From 30 to 50% of all patients in the United States having cataract extraction develop opacification of the posterior lens capsule within two years and require laser treatment with its own significant risk of complications. Of the patients having cataract surgery, 0.8% develop retinal detachments, from 0.6% to 1.3% were rehospitalized for corneal edema or required corneal transplantation and about 0.1% presented with endophthalmitis . Thus, aside from secondary cataract, about 2% of 1.3 million people, or 26,000 individuals in the United States annually develop serious complications as a result of cataract surgery. The aim of this investigation was to increase the safety and effectiveness of an individual intraocular lens (IOL) preventing an impairment in peroxide metabolism of the mature human cataractous lenses compared to normal lenses employing the specific nanotechnology coating which substitutes the inhibitory effect of the implantable device towards the active species of oxygen and the ability of IOL to regulate the H2O2 and lipid hydroperoxides levels in the surrounding medium. The implantation of IOLs with metabolic activity improves the capability of the surrounding ocular tissues to withstand oxidative stress induced in ocular humors by the photochemical and other metabolic reactions. The coated implantable medical device with thin film of platinum applied with magnetron sputtering, reacts as a body enzyme with deleterious peroxide compounds and free radical oxygen species in body fluids and tissue when said device is implanted into human body. The IOL having haptics coated with thin film of platinum, catalyzes the reduction of peroxide compounds to decrease their levels within the aqueous humor. Further, the coatings also scavenge toxic free radicals of oxygen, thus preventing cellular dysfunction resulting from oxidative attack. Coated IOLs according to the patented nanotechnology can address the vast majority of cataract surgery-induced complications, such as secondary cataract, intraocular inflammation (endophthalmitis) and foreign body reactions, cystoid macular oedema, corneal edema. The nanotechnology offers physicians and surgeons to develop and commercialize costeffective therapeutic medical implantable devices, products and support systems with metabolic activities for the treatment of ophthalmic diseases and of a wide range of pathological states and disorders which are treated by insertion of the implantable and prosthetic (polymeric) devices.

Recent Patent in Controlled Porosity Osmotic Pump by Alpesh Patel, Tarak Mehta, Mukesh Patel, Kanu Patel, Natvarlal Patel (66-72).
The porous osmotic pump based drug delivery system for excellent controlled release of drug for 24 hrs. The porous osmotic pump contains pore forming water soluble additives in the coating membrane, which after coming in contact with water, dissolve, resulting in an in situ formation of a microporous structure. The porous osmotic pump delivery from this system is not influenced by the different physiological factors. The present review is concerned with the patent study of drug release through controlled porous osmotic pump. This patent review is useful in knowledge of controlled porous osmotic pump for its application.

Co-Processed Excipients: A Patent Review by Nidhi Garg, Harish Dureja, Deepak Kaushik (73-83).
The introduction of high speed tableting machines and the preference of direct compression as a method of tableting have increased the demands on the functionality of excipients mainly in terms of flowability and compressibility. Co-processed excipients, where in, excipients are combined by virtue of sub-particle level interaction have provided an attractive tool for developing high functionality excipients. The multifold advantages offered by co-processed excipients such as production of synergism in functionality of individual components, reduction of company's regulatory concern because of absence of chemical change during co-processing and improvement in physico-chemical properties have expanded their use in the pharmaceutical industry. In the recent years, there has been a spurt in the number of patents filed on co-processed excipients. Hence, the present review focuses on co-processed excipients and their application in pharmaceutical industry. The worldwide databases of European patent office (http://ep.espacenet.com) and United States patent office (www.uspto.gov) were employed to collect the patents and patent applications. The advantages, limitations, basis for the selection of excipients to be co-processed, methods of co-processing and regulatory perspective of co-processed excipients are also briefly discussed.