Explore the clinical benefits and applications of sustained release drug delivery with this presentation. Access the findings from a technical feasibility study as well as a case study on sustained release microparticle formulation for a sensitive peptide.
This review article covers the detailed about cubosome. Cubosomes are single crystal structures, with visible unilamellar vesicles, dispersed lamellar liquid crystalline phase particles. Increasing polymer to monoolein ratios leads to formation of larger vesicles. Cubosomes are nanoparticles whose size ranges from 10 50nm in diameter they appear like dots square shaped, slightly spherical. Each dot corresponds to the presence of pore containing aqueous phase cubic phases in lipid water system in X ray scattering technique. and also covers some methods of preparation of cubosome along with there characterization methods like Cryo Transmission Electron Microscopy Cryo TEM , Small Angle X ray Scattering SAXS , Particle Size Distribution PSD . Application of cubosome like vehicle activity of biological substances, controlled release of solubilized substances, Treatment of skin, hair, and other body tissue. Melanoma cancer therapy on size delivery system is the key to target cancer through the enhanced permeability and retention effect. With some advantages of cubosome. Vishal B. Patond | Ananta B. Ghonge | Mahesh B. Narkhede "Cubosome - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-4 , June 2020, URL: https://www.ijtsrd.com/papers/ijtsrd31428.pdf Paper Url :https://www.ijtsrd.com/pharmacy/other/31428/cubosome-%E2%80%93-a-review/vishal-b-patond
This document provides an overview of protein and peptide drug delivery. It begins with definitions of proteins and peptides and descriptions of protein structure. It then discusses protein functions and challenges with delivering proteins and peptides. These challenges include low permeability, enzyme degradation, short half-life, and immunogenicity. The document outlines various barriers to protein delivery, including enzymatic barriers and barriers at the intestinal epithelium, capillary endothelium, and blood-brain barrier. It also discusses physicochemical properties of proteins and peptides that impact delivery. Finally, it reviews various routes of delivery such as parenteral, pulmonary, and transdermal routes and technologies used for delivery like liposomes, hydrogels, emulsions, and pumps.
1. The document discusses various parenteral controlled drug delivery systems including routes of administration, approaches for sustained release, and examples like long-acting penicillin, insulin, vitamin B12, and hormone preparations.
2. It describes types of implant drug delivery systems including biodegradable and non-biodegradable systems. Biodegradable polymers commonly used include PLGA, PLA, and PGA.
3. Ocular inserts are discussed as a type of implant, with insoluble and soluble inserts described. Insoluble inserts like Ocusert use rate-controlling membranes to provide constant drug diffusion over time.
Nanoparticle targeted drug delivery systemBINDIYA PATEL
This document discusses nanoparticles as subnanosized colloidal drug delivery systems ranging from 10-1000 nm in diameter. It defines nanoparticles and describes their basic concept of selectively delivering drugs to target tissues while restricting access to non-target tissues. The document outlines ideal characteristics of nanoparticles and various methods for their preparation, characterization, and evaluation. It provides examples of nanoparticle applications such as cancer therapy, intracellular targeting, vaccines, DNA delivery, and ocular delivery. The document concludes by listing references for further information on nanoparticles.
This document provides an overview of a seminar presentation on liposomes. It begins with an introduction defining liposomes as vesicles with an aqueous volume enclosed by a phospholipid bilayer. It then discusses the composition of liposomes, including the structure of phospholipids. Various methods for preparing liposomes are described, such as mechanical dispersion, freeze drying, sonication, and microemulsification. Liposomes can be classified based on their structure, preparation method, or composition. The document concludes by discussing techniques for characterizing liposomes, including evaluating their physical properties like size, surface charge, and drug encapsulation efficiency.
The document discusses microspheres, which are solid spherical particles made of polymeric substances that can encapsulate drugs. Microspheres range in size from 1-1000μm and enable controlled drug release. They were first developed in the 1930s and are now commonly used in pharmaceutical applications. Key manufacturing methods include single/double emulsion techniques, polymerization, coacervation, spray drying, and solvent extraction. Microspheres offer advantages like accurate dosing, protection of drugs, and controlled release profiles.
Cubosomes are liquid crystalline nanostructured particles formed from the self-assembly of amphiphilic molecules like monoolein. They have a bicontinuous internal structure divided into two separate but non-intersecting hydrophilic regions by a lipid bilayer. Cubosomes can be produced using either a "top-down" method by breaking up a bulk cubic phase or a "bottom-up" method by controlled crystallization from precursor solutions. Their interaction with model cell membranes is sensitive to small changes in surface charge, suggesting they could potentially be optimized to preferentially target cancer cells for drug delivery applications.
This review article covers the detailed about cubosome. Cubosomes are single crystal structures, with visible unilamellar vesicles, dispersed lamellar liquid crystalline phase particles. Increasing polymer to monoolein ratios leads to formation of larger vesicles. Cubosomes are nanoparticles whose size ranges from 10 50nm in diameter they appear like dots square shaped, slightly spherical. Each dot corresponds to the presence of pore containing aqueous phase cubic phases in lipid water system in X ray scattering technique. and also covers some methods of preparation of cubosome along with there characterization methods like Cryo Transmission Electron Microscopy Cryo TEM , Small Angle X ray Scattering SAXS , Particle Size Distribution PSD . Application of cubosome like vehicle activity of biological substances, controlled release of solubilized substances, Treatment of skin, hair, and other body tissue. Melanoma cancer therapy on size delivery system is the key to target cancer through the enhanced permeability and retention effect. With some advantages of cubosome. Vishal B. Patond | Ananta B. Ghonge | Mahesh B. Narkhede "Cubosome - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-4 , June 2020, URL: https://www.ijtsrd.com/papers/ijtsrd31428.pdf Paper Url :https://www.ijtsrd.com/pharmacy/other/31428/cubosome-%E2%80%93-a-review/vishal-b-patond
This document provides an overview of protein and peptide drug delivery. It begins with definitions of proteins and peptides and descriptions of protein structure. It then discusses protein functions and challenges with delivering proteins and peptides. These challenges include low permeability, enzyme degradation, short half-life, and immunogenicity. The document outlines various barriers to protein delivery, including enzymatic barriers and barriers at the intestinal epithelium, capillary endothelium, and blood-brain barrier. It also discusses physicochemical properties of proteins and peptides that impact delivery. Finally, it reviews various routes of delivery such as parenteral, pulmonary, and transdermal routes and technologies used for delivery like liposomes, hydrogels, emulsions, and pumps.
1. The document discusses various parenteral controlled drug delivery systems including routes of administration, approaches for sustained release, and examples like long-acting penicillin, insulin, vitamin B12, and hormone preparations.
2. It describes types of implant drug delivery systems including biodegradable and non-biodegradable systems. Biodegradable polymers commonly used include PLGA, PLA, and PGA.
3. Ocular inserts are discussed as a type of implant, with insoluble and soluble inserts described. Insoluble inserts like Ocusert use rate-controlling membranes to provide constant drug diffusion over time.
Nanoparticle targeted drug delivery systemBINDIYA PATEL
This document discusses nanoparticles as subnanosized colloidal drug delivery systems ranging from 10-1000 nm in diameter. It defines nanoparticles and describes their basic concept of selectively delivering drugs to target tissues while restricting access to non-target tissues. The document outlines ideal characteristics of nanoparticles and various methods for their preparation, characterization, and evaluation. It provides examples of nanoparticle applications such as cancer therapy, intracellular targeting, vaccines, DNA delivery, and ocular delivery. The document concludes by listing references for further information on nanoparticles.
This document provides an overview of a seminar presentation on liposomes. It begins with an introduction defining liposomes as vesicles with an aqueous volume enclosed by a phospholipid bilayer. It then discusses the composition of liposomes, including the structure of phospholipids. Various methods for preparing liposomes are described, such as mechanical dispersion, freeze drying, sonication, and microemulsification. Liposomes can be classified based on their structure, preparation method, or composition. The document concludes by discussing techniques for characterizing liposomes, including evaluating their physical properties like size, surface charge, and drug encapsulation efficiency.
The document discusses microspheres, which are solid spherical particles made of polymeric substances that can encapsulate drugs. Microspheres range in size from 1-1000μm and enable controlled drug release. They were first developed in the 1930s and are now commonly used in pharmaceutical applications. Key manufacturing methods include single/double emulsion techniques, polymerization, coacervation, spray drying, and solvent extraction. Microspheres offer advantages like accurate dosing, protection of drugs, and controlled release profiles.
Cubosomes are liquid crystalline nanostructured particles formed from the self-assembly of amphiphilic molecules like monoolein. They have a bicontinuous internal structure divided into two separate but non-intersecting hydrophilic regions by a lipid bilayer. Cubosomes can be produced using either a "top-down" method by breaking up a bulk cubic phase or a "bottom-up" method by controlled crystallization from precursor solutions. Their interaction with model cell membranes is sensitive to small changes in surface charge, suggesting they could potentially be optimized to preferentially target cancer cells for drug delivery applications.
Formulation & evaluation of Sustained release matrix tabletPrathamesh Patil
This document summarizes the formulation and evaluation of sustained release matrix tablets containing the drug levofloxacin. Matrix tablets were prepared using natural polymers like guar gum, karaya gum, and xanthan gum to achieve sustained release over 12 hours. Tablets were prepared by direct compression and evaluated for properties like weight variation, hardness, thickness, friability, and dissolution. Formulation F7, containing the polymers in a 40 mg ratio, provided 12 hours of drug release and was considered the optimized sustained release formulation.
Protein and-peptide-drug-delivery-systemsGaurav Kr
The document discusses protein and peptide drug delivery systems. It begins by defining proteins and peptides, noting that proteins are molecules composed of over 50 amino acids, while peptides are molecules composed of less than 50 amino acids. It then discusses how scientific advances in molecular and cell biology have led to the development of recombinant DNA and hybridoma technology to produce protein products. The document provides examples of marketed protein and peptide drugs and discusses challenges with delivering these drugs orally due to their large molecular size and susceptibility to enzymatic degradation. It explores approaches to protein and peptide delivery including non-parenteral systemic delivery methods and various considerations for developing delivery systems for these pharmaceuticals.
This document discusses crystallization, including its definition, importance, applications, theory, and types of crystallizers. Crystallization is the process where solid crystals form from a solution, melt, or gas. It is important for purifying and developing drugs to improve properties like stability, dissolution rate, and bioavailability. Crystallization is widely used in pharmaceutical manufacturing for purification, improved processing and physical stability, sustained release, and preparing active pharmaceutical ingredients with high yields. The major stages of crystallization are supersaturation of the solution, nucleation of crystal clusters and embryos, and crystal growth. Draft tube baffle and forced circulation crystallizers are described for their crystallization techniques.
This document discusses nanoparticles, which are sub-nanosized colloidal structures composed of synthetic or semi-synthetic polymers between 10-1000 nm in size. Nanoparticles can be nanocapsules or nanospheres depending on if the drug is confined in a cavity or dispersed in a matrix. They are classified based on their material and can be prepared through various polymerization or precipitation methods. Nanoparticles offer advantages like improved drug stability and targeting but also disadvantages like toxicity risks. The document outlines characterization techniques and applications in cancer therapy, vaccines, and crossing the blood brain barrier.
Sr no Contents
1 Introduction
2 Advantages and disadvantages
3 Types of nanoparticle
4 Classification of Nanoparticle
5 Polymers used in nanoparticles
6 Method of preparation
7 Evaluation of nanoparticles
8 Application of nanoparticles
9 References
Nanoparticles is derived from the Greek word Nano means extremely small.
Nanoparticles are sub Nano sized colloidal drug delivery systems .
Particle size ranges from 10-1000 nm in diameter .
They are made up of natural, synthetic or semi synthetic polymers carrying drugs or proteinaceous substances, i.e. antigen(s) .
Drugs are entrapped either in the polymer matrix as a particulates or solid solutions or may be bound to particle surface by physical adsorption or by chemical reaction.
Drug can be added during preparation of nanoparticles or to the previously prepared nanoparticles
Nanoparticles can act as controlled release system depending on their polymeric composition.
As a targeted drug carrier nanoparticles reduce drug toxicity
Less amount of dose required.
They enhance aqueous solubility of poorly soluble drug therefore increase its bioavailability, therapeutic efficacy and Reduces side effects.
Nanoparticles can be administer by various routes including oral, nasal, parenteral, intra-ocular etc.
A) AMPHIPHILIC MACROMOLECULE CROSS-LINKING
B) Polymerization method
C)Polymer precipitation method
Heat cross-linking
Chemical cross-linking
Emulsion chemical dehydration
By Crosslinking in W/O Emulsion
PH-induced aggregation
Counter ion induced aggregation
Emulsion polymerization a)Micellar nucleation and polymerization b)Homogenous nucleation and polymerization)
Dispersion polymerization
Interfacial polymerization
Emulsion solvent evaporation method
Double emulsion and evaporation method
Solvent displacement
Salting out
Nanoprecipitation
The document discusses various techniques for enhancing the solubility and dissolution of poorly soluble drug compounds. It begins by defining concepts like solubility, dissolution, and factors that affect them. Then it describes several techniques including physical modifications like particle size reduction and polymorphism, chemical modifications like changing pH and forming salts, and use of surfactants, microemulsions, and self-emulsifying drug delivery systems. Specific methods discussed in detail include nanosuspensions, nanomorph technology, and use of polymers for solubility enhancement.
Liposomes-Classification, methods of preparation and application Vijay Hemmadi
liposome preparation and application
A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Membranes are usually made of phospholipids, which are molecules that have a head group and a tail group
“Emulsion of emulsion”, “double or triple emulsion”
Dispersed phase contain smaller droplets that have the same composition as the external phase.
Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in order to travel from one phase to another – “Liquid Membrane System”
Two types: -
Oil-in-water-in-oil (O/W/O) emulsion system.
Water-in-oil-in-water (W/O/W) emulsion system.
X-ray diffraction is a technique used to determine the atomic structure of crystals. When X-rays strike the regular array of atoms in a crystal, they produce a pattern of diffracted rays. By measuring the angles and intensities of these diffracted beams, the crystal structure can be analyzed. X-ray crystallography is used across many fields to determine molecular structures, crystal structures, and physical properties of materials. It works by firing X-rays at crystalline samples and observing the diffraction patterns that emerge, which can then be analyzed using Fourier transforms to reveal details about atomic positions and electron densities within the crystal. Common applications of X-ray diffraction include phase identification, structural elucidation of organic and inorganic compounds, and
This document provides an overview of the freeze drying (lyophilization) process. It discusses the three main steps: freezing, primary drying, and secondary drying. Freezing involves cooling the material below its freezing point. Primary drying occurs under vacuum where water sublimates from the frozen material. Secondary drying removes unfrozen water under higher temperature and lower pressure. The document also describes the components and working of freeze drying equipment, including the refrigeration system, vacuum system, product chamber, and condenser. Common excipients used in lyophilized formulations are discussed, such as bulking agents, stabilizers, and buffers.
Reversed phase chromatography is an adsorption technique used to separate nonpolar substances. It works by having a nonpolar stationary phase and a polar mobile phase, opposite of normal phase chromatography. Molecules like proteins, peptides, and nucleic acids can be separated using reversed phase chromatography. The separation depends on the hydrophobic binding of solutes from the mobile phase to the hydrophobic ligands attached to the stationary phase. Common stationary phases use silica beads with attached alkyl hydrocarbon chains of varying lengths. Gradient elution with mixtures of water and organic solvents like acetonitrile or methanol is typically used for separation. Reversed phase chromatography has applications in preparative purification of proteins, peptides, and other biomolecules.
This document provides an overview of amorphous solid dispersions. It discusses glass transition temperature and how polymers can inhibit drug crystallization as a carrier matrix. Preparation methods like hot melt extrusion and solvent evaporation are described. Characterization techniques involve thermal analysis, spectroscopy and diffraction to analyze phase composition and molecular arrangement. In vitro tests examine the "spring and parachute" effect where drug dissolution increases initially before precipitation occurs without proper inhibition. Amorphous solid dispersions provide a formulation strategy for improving solubility of poorly water soluble drug candidates.
Dextran is a complex branched polysaccharide composed of glucose molecules used medicinally as an antithrombotic and plasma volume expander. It is produced by certain bacteria through fermentation of sucrose and has a variety of applications including use as an anticoagulant, plasma volume expander, and in microsurgery due to its antiplatelet and thrombolytic properties. Dextran comes in a range of molecular weights and has favorable properties such as water solubility, biocompatibility, and biodegradability making it suitable for medical and laboratory applications.
Ion exchange chromatography and gel permeation chromatography are discussed. Ion exchange chromatography separates molecules based on ionic interactions between charged molecules and oppositely charged sites on a stationary phase. Gel permeation chromatography separates molecules by size as larger molecules pass through porous beads faster than smaller molecules. Both techniques are useful for separating and analyzing biomolecules and polymers.
Gas chromatography is a technique used to separate and analyze mixtures that relies on the differential partitioning of analytes between a stationary and mobile phase. Key aspects of GC include vaporizing samples and carrying them through a column via an inert gas, where separation occurs based on interactions with the immobilized stationary phase. Common detectors measure changes in thermal conductivity, ionization, or other properties to identify separated analyte compounds and allow for qualitative and quantitative analysis of complex samples.
Microspheres are spherical & free flowing particles ranging in average particle size from 1 to 50 microns which consist of proteins or synthetic polymers. Some of the problems of overcome by producing control drug delivery system which enhances the therapeutic efficacy of a given drug. One such approach is using microspheres as carriers for drugs. The target site drug deliver with Specificity & maintain the concentration at site of interest without untoward effects. It will find the central place in novel drug delivery. Drugs can be targeted to specific sites in the body using microspheres. Degree of targeting can be achieved by localization of the drug to a specific area in body (for example in lungs), to a particular group of cells and even to the intracellular structures. The rate of drug release from the microspheres dictates their therapeutic action.
Lipid nanoparticles are a promising delivery system for mRNA vaccines. They consist of four main components - ionizable lipid, helper lipid, cholesterol, and PEG lipid. Three common types are described: lipoplexes which have low stability and efficiency; lipid nanoparticles which have a core-shell structure and superior properties; and lipid-polymer hybrids which combine lipids and polymers. Key factors in lipid nanoparticle design include size, surface charge, encapsulation efficiency, and lipid ratios. Various preparation methods can be used but microfluidic mixing provides high reproducibility. Characterization of size, stability, and encapsulation efficiency is important for mRNA delivery optimization.
parenteral drug delivery systemsSnehal pdds pptsnehal dhobale
This document provides information on parenteral controlled drug delivery systems. It discusses various types of injectable and implantable drug delivery systems including in-situ forming drug delivery systems, solutions, microspheres, liposomes, and suspensions that can provide controlled release of drugs through various mechanisms like dissolution, adsorption, encapsulation, and esterification. It also describes classification and examples of implantable drug delivery systems that use diffusion, activation by osmotic pressure or hydration, or feedback regulation to control drug release.
Oral lipid drug delivery system for poor water soluble drugsTanvi Shetty
Lipid-based drug delivery systems (OLDDS) have been used to improve oral absorption of poorly soluble drugs. These systems utilize lipid excipients such as triglycerides, surfactants, and co-solvents to enhance drug solubility and permeability. Several formulation approaches exist including self-emulsifying drug delivery systems (SEDDS), self-microemulsifying drug delivery systems (SMEDDS), liposomes, solid lipid nanoparticles, and lipid drug conjugates. OLDDS can improve drug bioavailability through controlled release in the gastrointestinal tract, interaction with enterocytes, and lymphatic uptake. Careful selection of lipid composition and excipients is important to maintain drug solubility upon dispersion and digestion.
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...MilliporeSigma
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Formulation & evaluation of Sustained release matrix tabletPrathamesh Patil
This document summarizes the formulation and evaluation of sustained release matrix tablets containing the drug levofloxacin. Matrix tablets were prepared using natural polymers like guar gum, karaya gum, and xanthan gum to achieve sustained release over 12 hours. Tablets were prepared by direct compression and evaluated for properties like weight variation, hardness, thickness, friability, and dissolution. Formulation F7, containing the polymers in a 40 mg ratio, provided 12 hours of drug release and was considered the optimized sustained release formulation.
Protein and-peptide-drug-delivery-systemsGaurav Kr
The document discusses protein and peptide drug delivery systems. It begins by defining proteins and peptides, noting that proteins are molecules composed of over 50 amino acids, while peptides are molecules composed of less than 50 amino acids. It then discusses how scientific advances in molecular and cell biology have led to the development of recombinant DNA and hybridoma technology to produce protein products. The document provides examples of marketed protein and peptide drugs and discusses challenges with delivering these drugs orally due to their large molecular size and susceptibility to enzymatic degradation. It explores approaches to protein and peptide delivery including non-parenteral systemic delivery methods and various considerations for developing delivery systems for these pharmaceuticals.
This document discusses crystallization, including its definition, importance, applications, theory, and types of crystallizers. Crystallization is the process where solid crystals form from a solution, melt, or gas. It is important for purifying and developing drugs to improve properties like stability, dissolution rate, and bioavailability. Crystallization is widely used in pharmaceutical manufacturing for purification, improved processing and physical stability, sustained release, and preparing active pharmaceutical ingredients with high yields. The major stages of crystallization are supersaturation of the solution, nucleation of crystal clusters and embryos, and crystal growth. Draft tube baffle and forced circulation crystallizers are described for their crystallization techniques.
This document discusses nanoparticles, which are sub-nanosized colloidal structures composed of synthetic or semi-synthetic polymers between 10-1000 nm in size. Nanoparticles can be nanocapsules or nanospheres depending on if the drug is confined in a cavity or dispersed in a matrix. They are classified based on their material and can be prepared through various polymerization or precipitation methods. Nanoparticles offer advantages like improved drug stability and targeting but also disadvantages like toxicity risks. The document outlines characterization techniques and applications in cancer therapy, vaccines, and crossing the blood brain barrier.
Sr no Contents
1 Introduction
2 Advantages and disadvantages
3 Types of nanoparticle
4 Classification of Nanoparticle
5 Polymers used in nanoparticles
6 Method of preparation
7 Evaluation of nanoparticles
8 Application of nanoparticles
9 References
Nanoparticles is derived from the Greek word Nano means extremely small.
Nanoparticles are sub Nano sized colloidal drug delivery systems .
Particle size ranges from 10-1000 nm in diameter .
They are made up of natural, synthetic or semi synthetic polymers carrying drugs or proteinaceous substances, i.e. antigen(s) .
Drugs are entrapped either in the polymer matrix as a particulates or solid solutions or may be bound to particle surface by physical adsorption or by chemical reaction.
Drug can be added during preparation of nanoparticles or to the previously prepared nanoparticles
Nanoparticles can act as controlled release system depending on their polymeric composition.
As a targeted drug carrier nanoparticles reduce drug toxicity
Less amount of dose required.
They enhance aqueous solubility of poorly soluble drug therefore increase its bioavailability, therapeutic efficacy and Reduces side effects.
Nanoparticles can be administer by various routes including oral, nasal, parenteral, intra-ocular etc.
A) AMPHIPHILIC MACROMOLECULE CROSS-LINKING
B) Polymerization method
C)Polymer precipitation method
Heat cross-linking
Chemical cross-linking
Emulsion chemical dehydration
By Crosslinking in W/O Emulsion
PH-induced aggregation
Counter ion induced aggregation
Emulsion polymerization a)Micellar nucleation and polymerization b)Homogenous nucleation and polymerization)
Dispersion polymerization
Interfacial polymerization
Emulsion solvent evaporation method
Double emulsion and evaporation method
Solvent displacement
Salting out
Nanoprecipitation
The document discusses various techniques for enhancing the solubility and dissolution of poorly soluble drug compounds. It begins by defining concepts like solubility, dissolution, and factors that affect them. Then it describes several techniques including physical modifications like particle size reduction and polymorphism, chemical modifications like changing pH and forming salts, and use of surfactants, microemulsions, and self-emulsifying drug delivery systems. Specific methods discussed in detail include nanosuspensions, nanomorph technology, and use of polymers for solubility enhancement.
Liposomes-Classification, methods of preparation and application Vijay Hemmadi
liposome preparation and application
A liposome is a tiny bubble (vesicle), made out of the same material as a cell membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Membranes are usually made of phospholipids, which are molecules that have a head group and a tail group
“Emulsion of emulsion”, “double or triple emulsion”
Dispersed phase contain smaller droplets that have the same composition as the external phase.
Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in order to travel from one phase to another – “Liquid Membrane System”
Two types: -
Oil-in-water-in-oil (O/W/O) emulsion system.
Water-in-oil-in-water (W/O/W) emulsion system.
X-ray diffraction is a technique used to determine the atomic structure of crystals. When X-rays strike the regular array of atoms in a crystal, they produce a pattern of diffracted rays. By measuring the angles and intensities of these diffracted beams, the crystal structure can be analyzed. X-ray crystallography is used across many fields to determine molecular structures, crystal structures, and physical properties of materials. It works by firing X-rays at crystalline samples and observing the diffraction patterns that emerge, which can then be analyzed using Fourier transforms to reveal details about atomic positions and electron densities within the crystal. Common applications of X-ray diffraction include phase identification, structural elucidation of organic and inorganic compounds, and
This document provides an overview of the freeze drying (lyophilization) process. It discusses the three main steps: freezing, primary drying, and secondary drying. Freezing involves cooling the material below its freezing point. Primary drying occurs under vacuum where water sublimates from the frozen material. Secondary drying removes unfrozen water under higher temperature and lower pressure. The document also describes the components and working of freeze drying equipment, including the refrigeration system, vacuum system, product chamber, and condenser. Common excipients used in lyophilized formulations are discussed, such as bulking agents, stabilizers, and buffers.
Reversed phase chromatography is an adsorption technique used to separate nonpolar substances. It works by having a nonpolar stationary phase and a polar mobile phase, opposite of normal phase chromatography. Molecules like proteins, peptides, and nucleic acids can be separated using reversed phase chromatography. The separation depends on the hydrophobic binding of solutes from the mobile phase to the hydrophobic ligands attached to the stationary phase. Common stationary phases use silica beads with attached alkyl hydrocarbon chains of varying lengths. Gradient elution with mixtures of water and organic solvents like acetonitrile or methanol is typically used for separation. Reversed phase chromatography has applications in preparative purification of proteins, peptides, and other biomolecules.
This document provides an overview of amorphous solid dispersions. It discusses glass transition temperature and how polymers can inhibit drug crystallization as a carrier matrix. Preparation methods like hot melt extrusion and solvent evaporation are described. Characterization techniques involve thermal analysis, spectroscopy and diffraction to analyze phase composition and molecular arrangement. In vitro tests examine the "spring and parachute" effect where drug dissolution increases initially before precipitation occurs without proper inhibition. Amorphous solid dispersions provide a formulation strategy for improving solubility of poorly water soluble drug candidates.
Dextran is a complex branched polysaccharide composed of glucose molecules used medicinally as an antithrombotic and plasma volume expander. It is produced by certain bacteria through fermentation of sucrose and has a variety of applications including use as an anticoagulant, plasma volume expander, and in microsurgery due to its antiplatelet and thrombolytic properties. Dextran comes in a range of molecular weights and has favorable properties such as water solubility, biocompatibility, and biodegradability making it suitable for medical and laboratory applications.
Ion exchange chromatography and gel permeation chromatography are discussed. Ion exchange chromatography separates molecules based on ionic interactions between charged molecules and oppositely charged sites on a stationary phase. Gel permeation chromatography separates molecules by size as larger molecules pass through porous beads faster than smaller molecules. Both techniques are useful for separating and analyzing biomolecules and polymers.
Gas chromatography is a technique used to separate and analyze mixtures that relies on the differential partitioning of analytes between a stationary and mobile phase. Key aspects of GC include vaporizing samples and carrying them through a column via an inert gas, where separation occurs based on interactions with the immobilized stationary phase. Common detectors measure changes in thermal conductivity, ionization, or other properties to identify separated analyte compounds and allow for qualitative and quantitative analysis of complex samples.
Microspheres are spherical & free flowing particles ranging in average particle size from 1 to 50 microns which consist of proteins or synthetic polymers. Some of the problems of overcome by producing control drug delivery system which enhances the therapeutic efficacy of a given drug. One such approach is using microspheres as carriers for drugs. The target site drug deliver with Specificity & maintain the concentration at site of interest without untoward effects. It will find the central place in novel drug delivery. Drugs can be targeted to specific sites in the body using microspheres. Degree of targeting can be achieved by localization of the drug to a specific area in body (for example in lungs), to a particular group of cells and even to the intracellular structures. The rate of drug release from the microspheres dictates their therapeutic action.
Lipid nanoparticles are a promising delivery system for mRNA vaccines. They consist of four main components - ionizable lipid, helper lipid, cholesterol, and PEG lipid. Three common types are described: lipoplexes which have low stability and efficiency; lipid nanoparticles which have a core-shell structure and superior properties; and lipid-polymer hybrids which combine lipids and polymers. Key factors in lipid nanoparticle design include size, surface charge, encapsulation efficiency, and lipid ratios. Various preparation methods can be used but microfluidic mixing provides high reproducibility. Characterization of size, stability, and encapsulation efficiency is important for mRNA delivery optimization.
parenteral drug delivery systemsSnehal pdds pptsnehal dhobale
This document provides information on parenteral controlled drug delivery systems. It discusses various types of injectable and implantable drug delivery systems including in-situ forming drug delivery systems, solutions, microspheres, liposomes, and suspensions that can provide controlled release of drugs through various mechanisms like dissolution, adsorption, encapsulation, and esterification. It also describes classification and examples of implantable drug delivery systems that use diffusion, activation by osmotic pressure or hydration, or feedback regulation to control drug release.
Oral lipid drug delivery system for poor water soluble drugsTanvi Shetty
Lipid-based drug delivery systems (OLDDS) have been used to improve oral absorption of poorly soluble drugs. These systems utilize lipid excipients such as triglycerides, surfactants, and co-solvents to enhance drug solubility and permeability. Several formulation approaches exist including self-emulsifying drug delivery systems (SEDDS), self-microemulsifying drug delivery systems (SMEDDS), liposomes, solid lipid nanoparticles, and lipid drug conjugates. OLDDS can improve drug bioavailability through controlled release in the gastrointestinal tract, interaction with enterocytes, and lymphatic uptake. Careful selection of lipid composition and excipients is important to maintain drug solubility upon dispersion and digestion.
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...MilliporeSigma
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
Hot melt extrusion with PVA – solubility enhancement, supersaturation perform...Merck Life Sciences
Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
PLGA is a biodegradable and biocompatible copolymer of PLA and PGA that is widely used for controlled drug delivery. It can be synthesized via melt polycondensation or ring opening polymerization to produce copolymers of varying molecular weight and properties. PLGA nanoparticles are effectively used to encapsulate drugs and provide sustained release over time. The drug release kinetics from PLGA nanoparticles are dependent on factors like polymer composition, drug loading, particle size and shape. PLGA degrades via hydrolysis of its ester linkages into biocompatible monomers. Alpha-1 antitrypsin encapsulated in PLGA nanoparticles is a promising approach for pulmonary delivery to treat lung diseases.
Excipients selection for high risk formulations Smita RajputMerck Life Sciences
Are you choosing the right excipients for your high risk application? Find out how to select the right excipients and enable your process optimization to improve the total cost of ownership.
In this webinar, you will learn:
• Selection of right excipients for high risk formulation is very critical step
• Low Endotoxin and low bioburden limits are important aspect while selecting raw materials
• Strong regulatory support is crucial for high risk formulation
Excipients selection for high risk formulations like parenteral and ophthalmic applications is very challenging. Excipients should be inert with high purity for such dosage forms because trace amounts of impurities present in excipients can interact with active pharmaceutical ingredient (API) which results in instability of the formulation. This presentation discusses how to select the right excipients for high-risk applications and gives guidance for process optimization by choosing the best combination of filters and excipients to improve the total cost of ownership.
Excipients selection for high risk formulations Smita RajputMilliporeSigma
Are you choosing the right excipients for your high risk application? Find out how to select the right excipients and enable your process optimization to improve the total cost of ownership.
In this webinar, you will learn:
• Selection of right excipients for high risk formulation is very critical step
• Low Endotoxin and low bioburden limits are important aspect while selecting raw materials
• Strong regulatory support is crucial for high risk formulation
Excipients selection for high risk formulations like parenteral and ophthalmic applications is very challenging. Excipients should be inert with high purity for such dosage forms because trace amounts of impurities present in excipients can interact with active pharmaceutical ingredient (API) which results in instability of the formulation. This presentation discusses how to select the right excipients for high-risk applications and gives guidance for process optimization by choosing the best combination of filters and excipients to improve the total cost of ownership.
FORMULATION AND EVALUATION OF GLIBENCLAMIDE MICROSPHERE DRUG DELIVERY SYSTEMArindam Chakraborty
The document discusses the formulation and evaluation of glibenclamide microsphere drug delivery system. The objective was to increase the drug's self-life by developing a microsphere delivery system. Two batches of glibenclamide microspheres were prepared using different polymers and manufacturing methods. Batch 2, prepared via spray congealing with agar polymer, showed more sustained release over 12 hours compared to Batch 1 and was considered the optimized formulation. In vitro drug release studies found Batch 2 followed zero-order kinetics. The microspheres were characterized and evaluated for properties like particle size, drug entrapment efficiency, and in vitro drug release kinetics. The study achieved sustained drug release to improve bioavailability and patient compliance.
Long Acting Injectables - A New Dimension for Proteins and PeptidesMilliporeSigma
This webinar discusses long-acting injectable microparticle formulations using SynBiosys® technology for sustained release of proteins and peptides. Case studies are presented on the sustained release of exenatide, a sensitive peptide, and a monoclonal antibody from biodegradable microparticles. Both proteins showed intact structure and biological activity for over a month in vitro and in animal studies, demonstrating the potential of this platform for long-term drug delivery of biologics.
Long Acting Injectables - A New Dimension for Proteins and PeptidesMerck Life Sciences
Access the recording: https://bit.ly/2xAaMba
Abstract:
Long acting injectables (LAI) have been around for decades for the delivery of small molecules and peptides to treat chronic and site-specific diseases. However, when it comes to more sensitive biological therapeutics the classical polylactide and polylactide/glycolide based systems suffer from several limitations (e.g. uncontrolled release kinetics, in situ pH drop, protein degradation) making them unsuitable. The SynBiosys® biodegradable polymeric microparticle technology combines all the features required for LAI formulations for biologics. In two case studies we will showcase sustained release formulations for peptides and proteins and demonstrate their potential via extensive in vitro and in vivo characterization.
This document discusses biodegradable polymers for use in drug delivery systems. It begins with an introduction to polymers and biodegradable polymers. It then covers various classes of biodegradable polymers investigated for controlled drug delivery including lactide polymers, polyanhydrides, poly-caprolactones, and polyphosphazenes. Factors affecting biodegradation and types of polymer drug delivery systems are also mentioned. The document provides an overview of important biodegradable polymers and their applications in drug delivery.
Nanoparticles are sub-nanosized colloidal structures composed of synthetic or semi synthetic polymers.
The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix.
Overcoming Challenges in Ophthalmic Formulations through Polymer Selection – ...Merck Life Sciences
Ophthalmic drug formulations are growing in importance due to the increased prevalence of eye-related disorders such as diabetic retinopathy and macular degeneration. However, ocular drug delivery is challenging due to unique anatomical and physiological barriers.
The low ocular bioavailability (<10%) of conventional ophthalmic formulations is driving the need for novel approaches to improve the delivery of the desired concentration, at the site of action, at a controlled rate.
This whitepaper provides an overview of polymers that can be used in ophthalmic formulations and highlights the advantages offered using polyvinyl alcohol (PVA) through case studies.
Find more information about excipients for liquid formulations on our website: https://www.sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/liquid-formulation
Recombinant proteins can be produced at large scale by expressing the gene of interest in a suitable expression system like bacteria, yeast, insect or mammalian cells. The recombinant protein is then isolated and purified using various chromatography techniques based on properties like size, charge, hydrophobicity. Common purification steps include capture using affinity or ion-exchange chromatography followed by polishing steps using techniques like size-exclusion chromatography to obtain highly purified protein. Rational design of purification schemes involves selecting orthogonal chromatography methods to separate the target protein from contaminants at each step based on resolution, capacity, and recovery needs.
Polymers are commonly used to coat pharmaceutical tablets and dosage forms. There are various types of coatings including conventional and enteric coatings. Conventional coatings can improve aesthetics, mask tastes, and modify drug release. Enteric coatings only dissolve in the intestines above pH 5.5-7 to protect acid-sensitive drugs. Common polymers for coatings include cellulose derivatives, acrylates, and polyvinyl derivatives. New techniques like hot melt extrusion can be used to produce enteric coatings. Coatings can provide benefits like targeted drug release and protection of actives or gastric mucosa.
Formulation and in-vitro Evaluation of Disclofenac Microspheres for Sustained...Sunil Vadithya
This document outlines a study to develop diclofenac microspheres for sustained drug delivery. Microspheres were prepared using various polymers via an ionotropic gelation method and evaluated for yield, particle size, drug entrapment efficiency, and in vitro drug release. Five formulations were developed using sodium alginate, HPMC, ethylcellulose, or eudragit alone or in combination. The microspheres were characterized for surface morphology, yield between 79-88%, and showed potential for sustained release of diclofenac.
The document discusses liquid sustained release systems. It describes various approaches to developing liquid sustained release formulations including suspensions, liquid crystalline phases, drug-resin complexes, in situ gel formation, microencapsulation, and emulsions/multiple emulsions. Key advantages of liquid sustained release systems are ease of administration to pediatric and geriatric patients, dose adjustment flexibility, and potentially better bioavailability than solid dosage forms. Evaluation methods for these systems include assessing properties like viscosity, drug entrapment efficiency, drug release profiles, and sterility. Potential applications mentioned include use of these formulations to deliver hormones, drugs for eye diseases, asthma medications, and others.
Formulation and evaluation of sustained release microspheres ofReshma Fathima .K
This document describes the formulation and evaluation of fenofibrate microspheres for sustained drug release. Fenofibrate microspheres were prepared using the emulsion-coacervation method with gelatin as the polymer. The microspheres were evaluated for particle size, drug entrapment efficiency, in vitro drug release, and stability. The results showed the microspheres had spherical morphology and successfully entrapped fenofibrate, providing sustained release over 12 hours. Thus, the fenofibrate microspheres developed in this study could be a promising approach for controlled delivery of this drug.
FORMULATION AND INVITRO EVALUATION OF COLON SPECIFIC DRUG DELIVERY SYSTEM BY ...alok prakash kar
The document describes the formulation and in vitro evaluation of a colon-specific drug delivery system containing metronidazole. Metronidazole tablets were prepared using different polymers like ethyl cellulose, cellulose acetate butyrate, and Eudragit polymers. The tablets were then coated with various polymer coating suspensions. The coated tablets were evaluated for film thickness, weight gain, hardness, disintegration time, and drug release. The results showed that the coating thickness and weight gain increased with increasing polymer concentration in the coating suspension. The coated tablets had suitable hardness and disintegration times while sustaining drug release in the acidic environment of the stomach.
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The Viscosity Reduction Platform: Viscosity-reducing excipients for improveme...MilliporeSigma
Protein viscosity is a major challenge in preparing highly concentrated protein formulations suitable for subcutaneous injection. Recently, the Viscosity Reduction Platform (VRP) was introduced and its technical key features and benefits for formulations were discussed. However, highly viscous solutions do not only pose a challenge when administering a drug to a patient, they can also impose technical limitations in the manufacturing process.
This white paper evaluates the effect of the excipients in the Viscosity Reduction Platform on ultrafiltration processes used to produce a highly concentrated formulation of a monoclonal antibody (mAb). Two filtration methods are demonstrated in this work.
Find more information about the Viscosity Reduction Platform on our website: https://www.sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Use of Excipients in Downstream Processing to Improve Protein PurificationMilliporeSigma
Excipients are used to improve the stability of protein-based therapeutics by protecting the protein against a range of stress conditions such as temperature changes, pH changes, or agitation. Similar stresses are applied to proteins during downstream purification. Shifts in pH during Protein A chromatography, subsequent incubations at low pH for virus inactivation, and changes in conductivity in ion exchange chromatography can lead to aggregation, fragmentation, or other chemical modifications of the therapeutic protein. Given the potential impact on the protein’s structural integrity, there is a need for approaches to reduce the risk presented by the conditions during downstream processing. For example, integration of a solution to prevent aggregation of proteins would be a more efficient strategy than implementing steps to remove multimeric forms.
This white paper highlights the results from a recent paper by Stange et. al., in which protein stabilizing excipients such as polyols, sugars, and polyethylene glycol (PEG4000) were used as buffer system additives. Effect of the excipients on elution patterns, stabilization of the monomer antibody, host-cell protein removal, virus inactivation rates and binding capacity of cation exchange chromatography were explored.
Exploring the protein stabilizing capability of surfactants against agitation...MilliporeSigma
Agitation of therapeutic protein solutions during manufacturing, shipping and handling is one of the major initiators for protein aggregation and particle formation during the life history of a protein drug. Adsorption of protein molecules to liquid-air interfaces leads to the formation of highly concentrated protein surface films. The rupture of these protein films due to various mechanical processes can then result in the appearance of protein aggregates and particles in the bulk solution phase.
One technique to stabilize proteins against stress induced by liquid-air interfaces is the use of non-ionic surfactants. About 91% of antibody formulations commercially available in 2021 contained a surfactant. Polysorbate 20 and 80, composed of a hydrophilic polyoxyethylene sorbitan and hydrophobic fatty acid esters, made up the largest part being employed in 87% of said formulations.
Despite their frequent use in parenteral drug products, concerns have been raised for decades about the application of polysorbates as surfactants in biopharmaceutical formulations. Autoxidation of polysorbate, caused by residual peroxides in polysorbates, can damage the proteins and can further drive the oxidative degradation of polysorbate. Chemical and enzymatic hydrolysis of polysorbate may lead to the formation of free fatty acid particles, which may become visible; and both mechanisms eventually lead to the reduction in polysorbate concentration. Therefore, the purpose of the current study was to compare various molecules for their capabilities to reduced agitation-induced protein aggregation and particle formation; and furthermore, investigate their underlying protein stabilizing mechanisms.
The Viscosity Reduction Platform: Viscosity Reducing Excipients for Protein F...MilliporeSigma
Protein viscosity is one of the major obstacles in preparing highly concentrated protein formulations suitable for subcutaneous injection.
This whitepaper examines how combining an amino acid with a second viscosity-reducing excipient circumvents adverse effects on protein stability and improves viscosity-reducing capacity.
To find more information about the Viscosity Reduction Platform, please visit our website: https://sigmaaldrich.com/products/pharma-and-biopharma-manufacturing/formulation/viscosity-reduction-platform
Characterization of monoclonal antibodies and Antibody drug conjugates by Sur...MilliporeSigma
The document discusses characterization of antibodies and antibody-drug conjugates (ADCs) using surface plasmon resonance (SPR). It provides details on:
1. Using SPR to characterize binding kinetics of ADCs and determine effects of different linker types and drug-antibody ratios on antigen binding. SPR shows reduced but detectable binding for ADCs versus the unconjugated antibody.
2. An application of SPR to study binding interactions of SARS-CoV-2 spike protein and mutants with the ACE2 receptor and anti-spike antibodies. This can aid understanding of viral mutations and inform vaccine and drug development.
3. SPR is proposed as a method to screen binding kinetics of spike protein mutants to evaluate effects
The Role of BioPhorum Extractables Data in the Effective Adoption of Single-U...MilliporeSigma
Regulatory expectation does require patient safety evaluations with supporting data for manufacturing components that directly come into contact with drug manufacturing process streams. Readily available extractables data can help manufacturers using singleuse technology to accelerate product qualifications, risk assessments and process optimization
This white paper guides you on how to save time and resources with supplier-provided single-use system extractables data and gives you an overview about the overall strategy for Extractables & Leachables. At the end you will find a case study.
Find more information about filters and single-use components on our website: https://www.sigmaaldrich.com/DE/en/services/product-services/emprove-program/emprove-filter-and-single-use-component-portfolio
The Future of Pharma- and Biopharmaceutical AuditsMilliporeSigma
The document discusses how COVID-19 has changed pharma and biopharmaceutical audits, with remote audits now accepted by regulatory authorities. It explores the benefits of different audit approaches like remote, virtual, and hybrid audits and the features that enable each. Regulatory bodies are adopting new guidance for remote inspections and assessments. Looking ahead, risk-based planning and digital solutions will allow the industry to conduct more flexible and agile audits, though on-site audits will still be necessary at times. Hybrid audits combining various approaches are positioned as the future of auditing.
Moving your Gene Therapy from R&D to IND: How to navigate the Regulatory Land...MilliporeSigma
Watch the recording of this presentation here: https://bit.ly/3SqOsoP
Novel therapies, including cell and gene therapies, continue to be central to innovation in healthcare and represent the fastest growing area of therapeutic medicine. As a consequence, the number of gene therapies undergoing clinical trials has increased significantly in the last five years.
Manufacturing processes for these novel therapeutics are very complex with a high risk of contamination. Regulatory agencies world-wide have responded by issuing guidance to outline their expectations for development and manufacture of cell and gene therapies. Currently, regulatory guidance is not harmonized globally and can often lead to confusion within industry and increased risk of non-compliance.
In this webinar, we'll answer:
• Which regulatory guidelines do you need to comply for your INDs?
• When do you start implementing GMPs and validated assays?
• How do you get your QC testing strategy ‘right the first time’?
• How do you ensure testing is not your rate limiting step for the IND submission?
Presented by:
Manjula Aysola, Senior Regulatory Consultant
Dr. Alison Armstrong, Sr. Director, Technical and Scientific Solutions
Identity testing by NGS as a means of risk mitigation for viral gene therapiesMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3RijkHC
Detailed description:
Imagine you’ve just completed a manufacturing run for your viral vector. Identity testing is performed to confirm the vector sequence. But when the results come back the data reveals unexpected sequence variants! With an appropriate risk mitigation testing strategy, this situation can be prevented.
The situation described above is not hypothetical, and happens more that you think, costing valuable time and resources.
Investigatory testing has shown that sequence variants present in starting materials (e.g. plasmids) are likely to make their way to the final product. Adequate identification of low-level variants with an appropriately sensitive method is critical in ensuring the quality of the final product. A risk-based testing strategy, in the context of identity, for viral vector manufacturing will be presented, focusing on key testing points. NGS assays for identity and variant detection will be highlighted due to their extremely sensitive nature compared to traditional approaches.
In this webinar, we'll explore:
• Regulatory requirements for identity testing
• NGS applications for identity testing as compared to traditional methods
• A case study on the impact of not establishing a proper risk-based testing strategy
Presented by: Bradley Hasson, Director of Lab Operations for NGS Services
Latest advancements of melt based 3D printing technologies for oral drug deli...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3A2WcH4
The application of polymer excipients in 3D printing manufacturing is usually limited due to the concerns of filament strength, high processing temperature and large scale manufacturing.
Latest technology developments are targeting a direct melt deposition to simplify the process and enable a constant and efficient process. Two different processing approaches will be presented:
The advanced melt drop deposition, where individual three dimensional geometries can be created by depostition of polymer droplets and the MED® 3D printing technology which allows by precise layer-by-layer deposition to produce objects with well-designed geometric structures.
In this webinar, you will learn:
• Latest advancements of melt based 3D printing approaches
• Application examples for the individual technologies
• Deep dive in the MED® 3D printing technology to design dedicated drug release profiles
Presented by:
Dr. Thomas Kipping, Head of Drug Carriers
Dr. Xianghao Zuo, Deputy Director of R&D, Triastek
CAR-T Manufacturing Innovations that Work - Automating Low Volume Processes a...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3NDNIKe
Automated, fit-for-purpose tools are essential in CAR-T processing to support sustainable manufacturing of clinical and market-approved cell therapy products. This webinar will discuss how the ekko™ Acoustic Cell Processing System uses acoustic technology as a touchless approach to manipulate cells, enabling a modular tool across the CAR-T manufacturing workflow. Typical performance of templated ekko™ System processes for DMSO washout of leukapheresis material, low volume and high cell concentrate for electroporation preparation, and harvest of expanded T cells will be reviewed.
This webinar will also give an early glimpse at the ekko™ Select System for unmatched T cell selection.
In this webinar, you will:
• Uncover how the ekko™ System supports the broad industrialization of cell therapy, with particular focus on how to achieve low volume, high concentrate cell product for critical transduction and transfection steps
• Discover how ekko™ System for wash and concentrate processes throughout the cell therapy workflow achieve high cell recovery, viability, and effective residual removal
• Preview to ekko™ Select, our cell therapy selection platform, to achieve unmatched ease-of-use with direct processing from leukopaks reducing the need for preparation steps
Presented by:
Benjamin Ross-Johnsrud, Acoustic Technology Expert
Robert Scott, Mechanical Engineer III
How does the ICH Q5A revision impact viral safety strategies for biologics?MilliporeSigma
The document discusses the expected revision of ICH Q5A guidance on viral safety of biotechnology products. Key points include:
1) ICH Q5A is being revised to address new biologic modalities like viral vectors and advances in manufacturing and detection methods.
2) The revision will provide more flexibility in viral clearance validation strategies and acceptance of alternative detection methods like PCR and HTS.
3) Challenges for viral safety of advanced manufacturing will also be discussed, as the original guidance does not address emerging approaches.
Improve Operational Efficiency by Over 30% with Product, Process, & Systems A...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3adaxWh
When implementing new automation systems, organizations must consider things like deployment time, user adoption, and costs.
They must also consider the cost of doing nothing – that is, what competitive advantage is lost in standing still? What time and quality is lost in repetitive, manual tasks rather than an automated, digital workflow? What operational efficiencies are lost?
In this webinar we examine how a product, process, and system agnostic automation platform can be deployed faster than traditional system specific software while bringing greater operational efficiencies (in many cases over 30% improvement).
To remain competitive in the market, biopharma manufacturers must adopt automation and digital technologies, but most plants still have island of automation consisting of independently functioning, standalone unit operations. This results in operational inefficiency, regulatory concerns, and a poor understanding of the process and product life cycle.
Taking the first, right step must include considering risks, costs, timelines, and technology alternatives. Traditional automation approaches tied to specific systems, processes, and products are, by their nature, limited; while an agnostic platform will address current biomanufacturing business challenges and ensure future readiness. With the right platform, a phased automation implementation can yield operational efficiency gains of up to 30% and improved product quality and regulatory compliance.
In this webinar, let's explore:
• Challenges of automation and digital technology adoption
• What a product, process, and system agnostic platform entails
• Applications and benefits of a process orchestration platform
• Ensuring future readiness with process orchestration
Presented by:
Braj Nandan Thakur, Global Product Manager - Automation
Insights from a Global Collaboration Accelerating Vaccine Development with an...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3Nbb5ug
Get insights and best practices from a multinational team establishing a platform for vaccine production. See how a long-term collaboration on a bench-scale process used to produce a Virus Like Particle (VLP) vaccine for SARS-CoV-2 was successfully converted to a robust GMP-compatible, scalable process.
The COVID-19 pandemic further emphasized the need for collaboration in the development of urgently needed vaccines and therapeutics. In this webinar, we take you behind the scenes of our collaboration with Technovax and Innovative Biotech in which a scalable VLP vaccine platform was optimized for use in a production facility in Nigeria in response to the need for local production of SARS-CoV-2 vaccines. The flexibility and robustness of the platform will enable its rapid deployment to support the West African pandemic readiness program. Initial development of the VLP process began in late 2019 and by March 2020, was already adapted for production of a SARS-CoV-2 vaccine.
In this webinar, you will learn:
• About building a priceless collaborative network with integrated solutions
• Virus-Like Particle Vaccines
• Process Development Overview and Challenges
• Pre-clinical Results and Next Steps
Presented by:
Jose M. Galarza, PhD,
President and Founder of TechnoVax
Naomi Baer,
Business development consultant, Emerging Biotech, BioProcess division
Youssef Gaabouri, Eng. ,
Associate Director, Head of Sales Middle East & Africa, BioProcess division
Risk-Based Qualification of X-Ray Sterilization for Single-Use SystemsMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3vQf0qv
In the single-use bioprocess industry, X-ray irradiation warrants consideration as an alternate sterilization technology. Using a risk-based qualification testing strategy is important when evaluating and implementing equivalent ionizing irradiation sterilization methods.
The urgent need for life-saving therapies as a result of the global pandemic has reinforced the criticality of flexibility in pharmaceutical manufacturing, including sterilization. The single-use bioprocess industry traditionally has employed gamma irradiation sterilization. X-ray irradiation is being considered as an additional sterilization technology for business and supply continuity. We will share a risk-based qualification testing strategy including Extractables and data generated to support comparability of gamma irradiation and X-ray irradiation as equivalent ionizing irradiation sterilization methods.
In this webinar, you will learn about:
• The comparison of gamma and X-ray irradiation sterilization
• A risk-based qualification test strategy
• Data evaluation of gamma versus X-ray sterilized single-use components
Presented by:
Monica Cardona,
Global Senior Program Manager
Paul Killian, Ph.D.,
R&D Director, Analytical Technologies
Rapid Replication Competent Adenovirus (rRCA) Detection: Accelerate your Lot ...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3MJ4u9V
Testing for presence of replication competent adenovirus (RCA) is a key component to ensure patient safety and a requirement for all biologicals manufactured using adenoviral vectors. For many adenoviral-based products, the RCA assay is a rate-limiting assay for lot release.
Join this webinar to learn about a rapid RCA detection assay currently in development, which combines a 7-day culture assay with a highly sensitive molecular endpoint specific for RCA. The method can detect presence of as little as 1 RCA in adenoviral vector material at an approximate concentration of 5x107 - 2x108 vector particles (VP)/mL, making it a suitable method to meet regulatory requirements while accelerating your lot release timelines.
In this webinar, you will learn about:
• Regulatory framework for adenoviral vector products
• Considerations for lot release testing of adenoviral-based therapies
• Advantages of a rapid method for RCA testing on production lot material
Presented by:
Axel Fun, Ph.D.,
Principal Scientist
Alberto Santana, MBA,
Product Manager, Biologics Biosafety Testing
The High Intensity Sweeteners Neotame and Sucralose: 2 Ways to ace the Patien...MilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3vQyN7K
Bitter medicines are an important issue, especially for pediatric applications. As several APIs have bitter tasting components, high intensity sweeteners for taste optimization are of great interest. Join our webinar to discover our new sweetener toolbox enabling safe and stable formulations.
Mask bitter aftertaste for a sweeter pill to swallow! Patients’ compliance and the therapeutic benefit are supported by a pleasant taste of pharmaceutical formulations. With the high intensity sweeteners Neotame and Sucralose, you have efficient tools at hand which are superior to other sweeteners in many aspects:
• excellent sugar-like taste profile
• outstanding sweetness factors
• use effectiveness
• enhanced stability
We will present our new toolbox of two high performance sweeteners and focus on aspects of stability, safety, the application in various dosage forms, and market perception.
In this webinar, you will learn:
• How to optimize the patients' taste experience of your pharmaceuticals
• How sweeteners can be differentiated by their sensory profiles and features
• How our new product offering Neotame can be effectively used in your targeted formulations
Presented by:
Almut von der Brelie,
Senior Manager Strategic Marketing, Excipients for Solid Applications
The Developability Classification System (DCS): Enabling an Optimized Approac...MilliporeSigma
This whitepaper by Dr. Daniel Joseph Price outlines how poorly soluble drug formulations can be designed using the developability classification system (DCS).
The DCS identifies the root cause of low solubility and enables lean, cost-effective and effective formulations to be developed.
#solubility #pharmaceuticalmanufacturing #oralsoliddosage #drugdevelopment
How to Accelerate and Enhance ADC TherapiesMilliporeSigma
In this webinar, you will learn about:
The advantages of using advanced intermediates to develop ADC therapies
How to increase ADC solubility and efficiency
Fast, small-scale ADC library generation
Seamless supply chain with reduced complexity and regulatory support
The ADCore product line offers versatile intermediates that simplify the synthesis of common ADC payloads (dolastatins, maytansinoids, and PBDs) by greatly reducing the number of synthetic steps. This translates to savings in development and manufacturing costs and shorter timelines to the clinic. To address the poor solubility of many ADC payloads, ChetoSensar™ was developed to significantly increase the hydrophilicity of the drug linker, which has been shown to also substantially increase the efficacy of ADCs and broaden the therapeutic window.
Lastly, the ADC Express™ service leverages conjugation chemistry and analytical expertise to help design and quickly synthesize sets of potential ADC therapies suitable for screening to simplify candidate selection and get ADC therapies to market faster.
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We are one of the top Massage Spa Ajman Our highly skilled, experienced, and certified massage therapists from different corners of the world are committed to serving you with a soothing and relaxing experience. Luxuriate yourself at our spas in Sharjah and Ajman, which are indeed enriched with an ambiance of relaxation and tranquility. We could confidently claim that we are one of the most affordable Spa Ajman and Sharjah as well, where you can book the massage session of your choice for just 99 AED at any time as we are open 24 hours a day, 7 days a week.
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Unlocking the Secrets to Safe Patient Handling.pdfLift Ability
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Chandrima Spa Ajman is one of the leading Massage Center in Ajman, which is open 24 hours exclusively for men. Being one of the most affordable Spa in Ajman, we offer Body to Body massage, Kerala Massage, Malayali Massage, Indian Massage, Pakistani Massage Russian massage, Thai massage, Swedish massage, Hot Stone Massage, Deep Tissue Massage, and many more. Indulge in the ultimate massage experience and book your appointment today. We are confident that you will leave our Massage spa feeling refreshed, rejuvenated, and ready to take on the world.
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The best massage spa Ajman is Chandrima Spa Ajman, which was founded in 2023 and is exclusively for men 24 hours a day. As of right now, our parent firm has been providing massage services to over 50,000+ clients in Ajman for the past 10 years. It has about 8+ branches. This demonstrates that Chandrima Spa Ajman is among the most reasonably priced spas in Ajman and the ideal place to unwind and rejuvenate. We provide a wide range of Spa massage treatments, including Indian, Pakistani, Kerala, Malayali, and body-to-body massages. Numerous massage techniques are available, including deep tissue, Swedish, Thai, Russian, and hot stone massages. Our massage therapists produce genuinely unique treatments that generate a revitalized sense of inner serenely by fusing modern techniques, the cleanest natural substances, and traditional holistic therapists.
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Long acting injectable microparticle formulation - a new dimension for peptides and proteins
1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
LONG-ACTING INJECTABLE MICROPARTICLE FORMULATIONS
A NEW DIMENSION FOR PROTEINS AND PEPTIDES
2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada
3. Need for sustained release drug
delivery systems for Biologics
Long-Acting Injectable Microparticle Formulations
3
Long-Acting Injectable Microparticle Formulations
Benefits of Sustained Release Drug Delivery
Clinical Benefits
Longer duration of action / less
frequent injections
Reduced side effects / toxicity due to
lower systemic levels
Enhanced therapeutic efficacy
Improved patient compliance
Applications
API with low t½ / small therapeutic
window
Oral incompatibility (proteins)
Chronic diseases
Site-specific drug delivery
Classical PLGA/PLA
formulations are not
suitable for sustained
release of biologicals due
to their rigidity and acidic
microenvironment
formation.
Currently no PLGA/PLA
polymer-based sustained
release drug delivery
products for protein
therapeutics FDA
approved.
4. Our Polymer Offering for Sensitive Peptides and Proteins
Long-Acting Injectable Microparticle Formulations
4
Small Molecules Peptides Proteins
< 1 kDa 1 – 10 kDa > 10 kDa
A versatile portfolio of biodegradable polymers and drug delivery systems to
formulate a fit for purpose drug product
PLGA / PLA (Expansorb®)
SynBiosys®
EXPANSORB® is a registered
trademark of Groupe Seqens,
Longjumeau, France
SynBiosys® is a registered trademark of
Innocore Pharmaceuticals, Groningen,
Netherlands
Long-Acting Injectable Microparticle Formulations
6. The SynBiosys® Polymer Platform
Long-Acting Injectable Microparticle Formulations
Prepolymer blocks Multi-block copolymer with
unique molecular architecture
Polyethylene
glycol
1,4-butanediol
6
(chain-extender)
1,4-butanediisocyanate
OH
HO
ppCP10C20
(amorphous & hydrophilic)
OH
HO
ppLL40
(Crystalline & rigid)
Long-Acting Injectable Microparticle Formulations
6
Toolkit Synthesis of multi-block copolymers
Initiators
ε-caprolactone
L-Lactide
Monomers
Customized biodegradable polymers designed for delivery of biologicals
Chain extender
7. The SynBiosys® Polymer Platform
Long-Acting Injectable Microparticle Formulations
7
Long-Acting Injectable Microparticle Formulations
Unlike traditional sustained release polymers, SynBiosys® provides a suitable
environment to maintain protein integrity and activity
• Hydrophilic Amorphous Domains
• Absorbs water and swells to form a hydrogel-like
structure
- Diffusion-controlled release
• Hydrophobic Crystalline Domains
• Physical X-link: provides structural integrity
- Control the degree of swelling
• Polymer Matrix Erosion and Degradation
• Degrades through hydrolysis
• No accumulation acidic degradation products
• No acidic microenvironment / in situ pH drop
• Multi-block co-polymers with phase-
separated morphology
• Hydrophilic amorphous domains
• Hydrophobic crystalline domains
9. Long-Acting Injectable Microparticle Formulations
9
Microspheres Solid Implants
Drug Eluting
Coatings
Injectable Gels
SynBiosys® biodegradable polymers are suitable for various long-acting (injectable)
sustained release drug delivery systems
Long-Acting Injectable Microparticle Formulations
SynBiosys® - Versatile Portfolio of Proprietary Drug Delivery Systems
10. Long-Acting Injectable Microparticle Formulations
10
Narrow Particle Size Distribution
Long-Acting Injectable Microparticle Formulations
SynBiosys® Microspheres
• Uniformly-sized microparticles
• Use of smaller needles (less painful injections)
• High API doses due to highly concentrated MSP
suspensions
11. From Feasibility Study to Scale-up
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
11
Feasibility studies
Small scale formulation development
0.5 – 25 g
Batch wise production
GLP tox and ph 1/2 clinical studies
Scale-up and reproducibility
25 250 g kg+
Semi-continuous production of microspheres followed by
batch wise hardening and drying
Unit operations that control key CQA are operated in continuous mode
resulting in a robust, well scalable process for reproducible production
12. Long-Acting Injectable Microparticle Formulations
SynBiosys® multi-block copolymers have amphiphilic character
Polymer chains distributed over Oil / Water interface during emulsification
Hydrophobic polymer blocks (poly(lactide) or poly(ε-caprolactrone)) dissolved in Oil Phase
Hydrophilic PEG chains in Water Phase
PEG-shielded water droplets protect protein from interacting with O/W interface
High Shear
Homogenizer
Polymer dissolved in DCM (O), protein
dissolved in aqueous buffer (W)
W/O (water-in-oil) emulsion with PEG chains in aqueous droplets
and hydrophobic polymer blocks and chains dissolved in DCM
Long Acting Injectable Microparticle Formulations
SynBiosys® Preserves Protein Integrity During Emulsification
12
14. Long-Acting Injectable Microparticle Formulations
14
Key Questions
Are SynBiosys® polymers and the
microparticle process suitable for
long term release of biologics?
Can biologics be encapsulated and
released structurally intact?
Can drug release kinetics of
biologics be tuned?
Are the in vivo released biologics
structurally intact, biologically
active and therapeutically
effective?
2nd
1st
High molecular
weight proteins
Sensitive peptide
Objective
Evaluate the SynBiosys® Technology Platform
of advanced biodegradable drug delivery systems
for sustained release of peptides and
biologicals.
Case Studies
Long-Acting Injectable Microparticle Formulations
Technical Feasibility Study
* https://s3-us-west-2.amazonaws.com/drugbank/protein_structures/full/DB01276.png?1452829397
*
16. Cumulative Exenatide Release
0 1 0 2 0 3 0 4 0 5 0 6 0
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
E
x
e
n
a
t
i
d
e
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
t o t a l E X T
i n t a c t E X T
Bydureon® shows a typical release
profile of PLGA microspheres
low initial burst
lag-phase
Bulk drug release between days
25-35
65% of the released Exenatide
remained intact
Bydureon® was used
for validation of the analytical
methods
as a reference formulation
Long-Acting Injectable Microparticle Formulations
16
Bydureon®: PLGA-based Exenatide Sustained Release Microparticles
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
17. Long-Acting Injectable Microparticle Formulations
17
0 7 1 4 2 1 2 8 3 5
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
C
u
m
u
l
a
t
i
v
e
R
e
l
e
a
s
e
[
%
]
Formulation Development – Tunability of Release Rate
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
Exenatide release kinetics
controlled by varying polymer composition
Tools to control drug release
• Polymer
- swelling degree
- degradation rate
• Microencapsulation process
Variables for Fine-Tuning
• PEG molecular weight
• PEG content
• Co-monomer type
• Co-monomer weight fraction
• Block ratio
• Molecular weight
18. 0 7 1 4 2 1 2 8 3 5 4 2
0
2 5
5 0
7 5
1 0 0
T im e [ d ]
E
x
e
n
a
t
i
d
e
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
t o t a l E X T
i n t a c t E X T
Long-Acting Injectable Microparticle Formulations
18
4 weeks Formulation (IC-4wF)
Exenatide is compatible with
SynBiosys® polymers and the
microparticle preparation
process yielding monodisperse
particles
Exenatide can be loaded in
microparticles with high EE
(86%)
Exenatide released from
microparticles remains intact
(70-78%)
Cumulative Drug Release – Animal Trial Material (ATM) Formulation
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
Mean values of n = 3 are shown ± SD
19. Long-Acting Injectable Microparticle Formulations
19
Mean values of n = 6 animals/group are shown ± SEM, LOQ = 0.112 ng/ml
Plasma Pharmacokinetics of 4 weeks Formulation (IC-4wF) (single s.c. administration)
7 1 4 2 1 2 8 3 5 4 2 4 9
0
2 0
4 0
6 0
T im e a f t e r a d m i n i s t r a t io n [ d ]
E
X
T
p
l
a
s
m
a
c
o
n
c
e
n
t
r
a
t
i
o
n
[
n
g
/
m
L
]
0 . 8 m g / k g E X T
4 . 0 m g / k g E X T
8 . 0 m g / k g E X T
B y d u r e o n - 2 . 0 m g / k g E X T
Dose-dependent plasma levels of Exenatide
No lag-phase and sustained release of API for up to 23 days
Plasma Levels after s.c. Injection of ATM Formulations
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
20. Continuous glucose-lowering effects and reduced HbA1c values demonstrate that the
steadily released peptide is biologically active and in an intact form
Long-Acting Injectable Microparticle Formulations
20
Non-fasting blood glucose (NFBG) levels
Long-Acting Injectable Microparticle Formulation for a Sensitive Peptide - Exenatide
0 7 1 4 2 1 2 8 3 5 4 2
- 7 5
- 5 0
- 2 5
0
2 5
5 0
T im e a f t e r a d m i n i s t r a t io n [ d ]
C
h
a
n
g
e
i
n
N
F
B
G
[
%
]
B
Y
D
,
P
-
O
,
I
C
-
4
w
F
B
Y
D
B
Y
D
B
Y
D
I C - 4 w F - 1 x 0 . 8 m g / k g E X T
B y d u r e o n - 4 x 2 . 0 m g / k g E X T
P o ly m e r - o n ly
I C - 4 w F - 1 x 8 . 0 m g / k g E X T
*
*
*
*
* *
*
*
* *
* *
* * *
*
* *
In vivo Studies – Pharmacological Efficacy in Diabetic Rats
% Glycated Hemoglobin A (HbA1c)
N
o
t
r
e
a
t
m
e
n
t
P
o
l
y
m
e
r
-
O
n
l
y
B
y
d
u
r
e
o
n
(
4
x
2
.
0
m
g
/
k
g
)
I
C
-
4
w
F
(
1
x
8
.
0
m
g
/
k
g
)
I
C
-
4
w
F
(
1
x
0
.
8
m
g
/
k
g
)
0
5
1 0
1 5
B
l
o
o
d
H
b
A
1
c
[
%
]
d ia b e t ic
n o n - d i a b e t ic
* *
21. Case Study II
Sustained release microparticle
formulation for a High molecular
Weight Protein
22. Long-Acting Injectable Microparticle Formulations
22
Proof of Concept along the Pharma Development Path
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
In vivo
Studies
0 5 1 0 1 5 2 0 2 5 3 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
P
l
a
s
m
a
l
e
v
e
l
m
A
b
X
[
µ
g
/
m
L
]
8 m g m A b X - M S P s s . c .
1 m g m A b X - M S P s s . c .
4 m g m A b X - M S P s s . c .
PK in healthy mice
6
Formulation
Development
@ Innocore
1
In vitro
Release 0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
T im e p o in t [ d a y s ]
m
A
b
X
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
I n t a c t m A b X
T o ta l m A b X
2
DiFi cells
4 Methods
for Integrity
Testing
3
0 5 1 0 1 5 2 0 2 5
0
2 0 0
4 0 0
6 0 0
8 0 0
0 . 0
0 . 2
0 . 4
0 . 6
0 . 8
1 . 0
T im e p o in t [ d a y s ]
m
A
b
X
[
µ
g
/
m
L
]
F
r
a
c
t
i
o
n
f
o
l
d
e
d
T o t a l m A b X ( S E C )
m A b X F r a c t i o n f o ld e d ( F l . S p e c . )
I n t a c t m A b X ( S E C )
I n t a c t m A b X ( E L I S A )
m A b X F r a c t i o n f o ld e d ( C D )
Production
Animal Trial
Material (ATM)
5
Cell-based
Activity Assay
4
23. Long-Acting Injectable Microparticle Formulations
Formulation Development – Tunability Drug Release
Sustained release of mAbB from days to weeks is feasible and highly tunable
Release can be steered by
Blend ratio (fraction PEG3000 relative to PEG1000)
Composition of crystalline block (poly(L-Lactide) vs
poly(p-dioxanone)
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
23
Blends of
• 50CP10C20-LL40
• 50CP30C40-LL40
Blends of
• 50CP10C20-D28
• 50CP30C40-D28
mAbB in vitro release kinetics mAbB in vitro release kinetics
24. Long-Acting Injectable Microparticle Formulations
Formulation Development – Microparticle Loading
Microspheres can be loaded with at least 25wt% mAbB and still exhibit
sustained release kinetics
Effect of mAbB loading on release rate
Water-free W/O/O Process
Quick preparation method
High loading & encapsulation
efficiencies
Low control over particle size
distribution
Fast screening
Fast in vivo
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
24
25. Long-Acting Injectable Microparticle Formulations
25
mAbX is compatible with
SynBiosys® polymers and
microparticle preparation
process
mAbX loading in microparticles
is 14.9%
mAbX released from
microparticles remains intact
(96%)
Linear release kinetics for up
to 10 days
0 5 1 0 1 5 2 0 2 5
0
2 0
4 0
6 0
8 0
1 0 0
T im e p o in t [ d a y s ]
m
A
b
X
c
u
m
u
l
a
t
i
v
e
r
e
l
e
a
s
e
[
%
]
I n t a c t m A b X
T o ta l m A b X
Cumulative mAbX in vitro release (IVR)
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
Formulation Development – ATM Formulation
26. 5
4
1
2
Functional cell-based
Assay
Ability of mAbX to inhibit
growth of DiFi colorectal
cancer cells
Fluorescence spectroscopy
Tertiarty structure intergrity
of mAbX
Receptor binding ELISA
Quantification of functional
mAbX
SE-HPLC
Quantification and
aggregation/fragmentation of
mAbX
Circular dichroism spectroscopy
Secondary structure integrity of mAbX
3
Long-Acting Injectable Microparticle Formulations
26
Analysis Strategy of mAbX Integrity after in vitro Release (IVR)
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
27. mAbX Integrity: Fluorescence and Circular Dichroism Spectroscopy
Long-Acting Injectable Microparticle Formulations
27
Calculation of Fraction Folded to simplify comparison between different methods
Fluorescence spectroscopy
Demonstrates the tertiarty structure intergity
Circular dichroism
Demonstrates secondary structure intergity
3 0 0 3 5 0 4 0 0 4 5 0
0 . 0
0 . 5
1 . 0
1 . 5
/ n m
N
o
r
m
a
l
i
z
e
d
f
l
u
o
r
e
s
c
e
n
c
e
i
n
t
e
n
s
i
t
y
/
a
.
u
.
S e t 1 , S a m p l e 1
S e t 1 , S a m p l e 2
S e t 1 , S a m p l e 3
S e t 1 , S a m p l e 4
S e t 1 , S a m p l e 5
S e t 1 , S a m p l e 6
S e t 1 , S a m p l e 7
0 5 1 0 1 5 2 0
3 3 0
3 3 5
3 4 0
3 4 5
3 5 0
3 5 5
T im e / d a y s
M
a
x
/
n
m
n a t iv e m A b X
c o m p le t e ly
u n f o ld e d m A b X
5 1 0 1 5
- 3 0 0 0
- 2 0 0 0
- 1 0 0 0
0
T im e / d a y s
/
d
e
g
c
m
2
d
m
o
l
-
1
c o m p le t e ly
u n f o ld e d m A b X
n a t iv e m A b X
2 2 0 2 4 0 2 6 0 2 8 0
- 4 0 0 0
- 2 0 0 0
0
2 0 0 0
/ n m
d
e
g
c
m
2
d
m
o
l
-
1
S e t 1 , S a m p le 1
S e t 1 , S a m p le 2
S e t 1 , S a m p le 3
S e t 1 , S a m p le 4
S e t 1 , S a m p le 5
S e t 1 , S a m p le 6
𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝐹𝑜𝑙𝑑𝑒𝑑 =
𝑥 − 𝜆𝑀𝑎𝑥, 𝑑𝑒𝑛𝑎𝑡.
𝜆𝑀𝑎𝑥, 𝑛𝑎𝑡𝑖𝑣𝑒 − 𝜆𝑀𝑎𝑥, 𝑑𝑒𝑛𝑎𝑡.
𝑥100
𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝐹𝑜𝑙𝑑𝑒𝑑 =
𝜃218 𝑛𝑚 − 𝜃218 𝑛𝑚, 𝑑𝑒𝑛𝑎𝑡.
𝜃218 𝑛𝑚, 𝑛𝑎𝑡𝑖𝑣𝑒 − 𝜃218 𝑛𝑚, 𝑑𝑒𝑛𝑎𝑡.
𝑥100
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
28. Integrity of mAbX Released from Microparticles
Long-Acting Injectable Microparticle Formulations
Preserved integrity & biological activity of released mAbX demonstrated with five
orthogonal analytical methods
mAbX in vitro release mAbX Integrity
0 5 1 0 1 5 2 0 2 5
0
2 0 0
4 0 0
6 0 0
8 0 0
T im e p o in t [ d a y s ]
I
V
R
o
f
m
A
b
X
[
µ
g
/
m
L
]
I n t a c t m A b X ( E L I S A )
I n t a c t m A b X ( S E C )
T o t a l m A b X ( S E C )
0 5 1 0 1 5 2 0
5 0
7 5
1 0 0
1 2 5
5 0
7 5
1 0 0
1 2 5
T im e p o in t [ d a y s ]
F
r
a
c
t
i
o
n
F
o
l
d
e
d
[
%
]
R
a
t
i
o
t
o
I
C
5
0
o
f
r
e
f
e
r
e
n
c
e
[
%
]
D i f i A s s a y F S C D
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
28
29. Long-Acting Injectable Microparticle Formulations
Pharmacokinetic Study in Healthy NMRI Mice
Plasma Pharmacokinetics of mAbX-MSPs (single s.c. administration)
0 5 1 0 1 5 2 0 2 5 3 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
T im e a f t e r a d m in is t r a t io n [ d ]
P
l
a
s
m
a
l
e
v
e
l
m
A
b
X
[
µ
g
/
m
L
]
8 m g m A b X - M S P s s . c .
1 m g m A b X - M S P s s . c .
4 m g m A b X - M S P s s . c .
Mean values of n = 6 animals/group are shown ± SEM
Amount of mAbX released from microparticle formulations is dose-dependent
mAbX can be detected in plasma samples by a functional binding ELISA
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
29
31. Long-Acting Injectable Microparticle Formulations
31
Conclusion
SynBiosys® polymers and the microsphere encapsulation process are compatible
with sensitive peptides and with high molecular weight proteins such as
monoclonal antibodies.
Linear release of peptide and monoclonal antibody from weeks to several months
in vitro.
In vitro released monoclonal antibody with high structural integrity as confirmed
by five orthogonal methods.
Immunogenic potential of SynBiosys®-based peptide and protein microparticles is
very low.
Controlled Release of biologically active monoclonal antibody and therapeutically
effective peptide was demonstrated in vivo.
Long-Acting Injectable Microparticle Formulation
34. Long-Acting Injectable Microparticle Formulations
34
Source:
EvaluatePharma
Long-Acting Injectable Microparticle Formulations
Significant growth of biological
therapeutics
2018 WW sales 243 $bn
2024 WW predicted sales 388 $bn
Biotech product sales overtake
conventional product sales in the top 100
product by sales in 2018 for 1st time
34%
66% 53%
47% 50%
50%
Biologics
within
Top 100 Sales
Growing importance of biologics drugs drives strong demand for drug delivery systems
for parenteral (sustained) release of protein therapeutics
Worldwide Prescription Drug Sales
Rapidly Increasing Significance of Biologics
35. Long-Acting Injectable Microparticle Formulations
Initiators
Polyethyleneglycol 1,4-butanediol
1,4-butanediisocyanate
Chain extender
Catalyst
Tin octanoate
Glycolide Lactide ε-caprolactone p-dioxanone
Monomers
Well-known, clinically-proven safe monomers and chemicals
Excellent track record in regulatory approved and marketed biomedical devices,
combination products and pharmaceutical drug delivery products
Long-Acting Injectable Microparticle Formulations
35
Monomers and Chemicals
36. Polyether Ester Urethane multi-block Copolymers
Long-Acting Injectable Microparticle Formulations
[ ---------------Hydrophilic block-------------]
PCL PEG PCL
[ ---------------Hydrophobic block------------------]
Variables
• Polyester monomer type
• Polyester monomer ratio
• Polyester block length
• PEG Molecular weight
• PEG/Polyester ratio
• Hydrophilic block length
PLA BDO PLA
Variables
• Polyester monomer type
• Polyester monomer ratio
• Polyester block length
• PEG/Polyester ratio
• Hydrophobic block length
UL
H—O-(CH2)5-C—O-(CH2CH2O)n—C-(CH2)5-O—C-N-(CH2)4-N-C—O-CH-C—O-(CH2)4-O—C-CH-O—H
O
=
O
=
O
=
O
=
H
ι
H
ι
I
CH3
O
=
O
=
[ ] ]
[ [ [
] ]
---PCL--- ------ PEG ------ ---PCL--- ----- BDI --------PLA----- BDO -- --PLA--
I
CH3
UL UL
Long-Acting Injectable Microparticle Formulations
36
37. SynBiosys® Platform - Polymer Nomenclature
Long-Acting Injectable Microparticle Formulations
37
Long-Acting Injectable Microparticle Formulations
50 C P10C20-LL40
PEG with molecular
weight 1000 g/mol
Polycaprolactone (PCL)
Weight percentage of
polycaprolactone-PEG
prepolymer
Poly(L-lactide) prepolymer with
molecular weight 4000 g/mol
PCL-PEG prepolymer with
molecular weight 2000 g/mol
38. 1. Combo Dual Therapy stent
Sirolimus-eluting coronary stent
Anti CD34 antibody coating
SynBiosys® polymer coating
Drug elution in 30 days
Full and complete polymer resorption
within 90 days
Proven clinical safety
Regulatory approval since 2013 (CE)
Clinically Validated Polymer Platform
Long-Acting Injectable Microparticle Formulations
Combo
®
is
a
registered
trademark
of
OrbusNeich
Proven clinical safety – Combo® sirolimus eluting dual therapy stent:
approved and marketed since 2013 by OrbusNeich
Long-Acting Injectable Microparticle Formulations
38
39. • Degradation mechanism and degradation products similar to commonly used biodegradable polyester
used in marketed products
• Extensive ISO-10993 biocompatibility / toxicity data package
• In vivo biocompatibility & degradation (implants, microspheres, coatings)
Various RoA: subcutaneous, intramuscular, intra-articular, intravitreal, intracardiac
Multiple species: rats, rabbits, mini-pigs, pigs, horses, primates
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
Monomer Degr. product Excreted as Route
Lactic acid Pyruvic acid CO2 + H2O Urine, breath
Glycolic acid Pyruvic acid CO2 + H2O Urine, breath
ε-Caprolactone -hydroxy heaxanoic acid -hydroxy heaxanoic acid Urine
p-Dioxanone 2-hydroxy ethoxy acetic acid
2-hydroxy ethoxy acetic
acid
Urine
PEG PEG PEG Urine
1,4-Butanediisocyanate
1,4-Butanediamine
(putrescine)
1,4-Butanediamine Urine, breath
1,4-Butanediol 1,4-Butanediol 1,4-Butanediol Urine
39
• Proven clinical safety – Combo® Dual Therapy Stent approved and marketed since 2013
Biocompatible Polymer Platform and Safe Degradation Products
40. 5 µm SynBiosys® Monospheres concentrated in
macrophages
Phagocytosis = extensive foreign body reaction
Long-Acting Injectable Microparticle Formulations
SynBiosys® Microspheres after 4 weeks SC (rats, ED-1 staining)
No phagocytosis of monodisperse 30 µm
SynBiosys® Microspheres
40
Reduced Immune Response due to Absence of small Particles
41. Long-Acting Injectable Microparticle Formulations
Use of smaller needles (less painful injections)
High API doses due to high MSP concentration
Long-Acting Injectable Microparticle Formulations
41
Superior Injectability due to uniformly-sized Microspheres
42. Preclinical Development and cGMP Manufacturing
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
42
API
&
TPP
Feasibility study
Scale-up for
GLP tox studies
Clinical
Trials
Commercial
Manufacturing
& Sales
Customer
SynBiosys®
DD System
• Optimization
• Scale-up
• Analytical
validation
• GLP tox material
production
• Stability testing
CTM production
(GMP)
• Tech Transfer
• cGMP production
clinical supplies
• QC testing
• Stability studies
• Analytical
development
• Formulation
development
• ATM production
• Stability testing
POC in vivo PK/PD GLP tox studies
Phase I/II clinical
studies
43. Scale-up Batch Sizes
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
43
API
&
TPP
Feasibility study
Scale-up for
GLP tox studies
Clinical
Trials
Commercial
Manufacturing
& Sales
Customer
SynBiosys®
DD System
CTM production
(GMP)
POC in vivo PK/PD GLP tox studies
Phase I/II clinical
studies
1-10 g Scale
25 – 250g 50 g - 1 kg
Non-GLP Quality
GLP GMP
44. Scale-up – Critical Quality Attributes
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
44
Polymer
solution
Protein
solution
Primary
emulsification
Aq. PVA solution
(Continuous phase)
Membrane
emulsification
Primary solvent
removal
Concentrating, washing
(and drying)
Powder
filling
Secondary solvent
removal
Washing media
Additives: bulking and
wetting agents,
surfactants, etc
Critical quality attributes
• Particle size (distribution)
• Protein content (encapsulation efficiency)
• Release kinetics
• Protein purity / integrity/ activity
• Protein-related impurities
• Internal morphology
• Surface morphology
• Protein distribution in microparticle
• Endotoxins
Critical quality attributes
• Residual solvent
• Residual moisture
• Particle size distribution
• Protein content (encapsulation efficiency)
• Endotoxins, sterility
• Resuspension behaviour
• Syringeability
• Stability
Suspension filling
and lyophilization
Key CQA
Critical process &
formulation
parameters
DoE
45. Scale-up – Batch-to-Batch Consistency
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
Particle size distribution (laser diffraction))
Robust, reproducible and well scalable process
45
46. Drug Type Maximum
microsphere
suspension
concentration
Maximum drug
load in
microsphere
Maximum drug dose (mg)
1 mL SC (≤ 2 mL) IM (≤ 4 mL)
mg MSP/mL mg API/g MSP mg API/mL mg API mg API
SMD 400 400 (40%) 160 ≤ 320 ≤ 640
Peptide 400 200 (20%) 80 ≤ 160 ≤ 320
Protein 400 150 (15%) 60 ≤ 120 ≤ 240
Antibody 300 250 (25%) 75 ≤ 150 ≤ 300
Calculation of maximum API dose of microsphere dosage form
Long-Acting Injectable Microparticle Formulations
Long-Acting Injectable Microparticle Formulations
46
Notes
Microspheres (MSP) are administered as a suspension of microparticles in reconstitution medium (WFI with
aqueous diluent containing CMC)
The max dose for small molecule drugs (SMD) represents lipophilic SMD. Lipophilic SMD are easy to
encapsulate due to their low aqueous solubility. Hydrophilic SMD are more challenging to encapsulate due
to their high aqueous solubility. As a consequence max doses are significantly lower (10-20% loading
400 mg/MSP/mL x 10-20% loading 40-80 mg/mL).
Peptides, proteins and antibodies are well soluble lower maximum drug load in MSP
47. Long-Acting Injectable Microparticle Formulations
Immunogenicity & Toxicology
IFN-γ
Interferones
TNF-α
Tumor necrosis
factors
MIP-1α
MIP-1β
RANTES
MIP-2
LIX
MCP-1
Eotaxin
IP-10
KC
Chemokines
IL-1α
IL-1β
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9
Interleukins
M-CSF
VEGF
G-CSF
GM-CSF
Colony stimulating
factors
(Growth factors)
Cytokines
IL-10
IL-12 (p40)
IL-12 (p70)
LIF
IL-13
IL-15
IL-17
MIG
After 24h, plasma levels of one (G-CSF) out of 32 cytokines elevated dose-
dependently after administration of formulations containing microparticles
0 1 0 2 0 3 0
0
5
1 0
1 5
2 0
2 5
T im e a f t e r a d m in is t r a t io n [ h ]
P
l
a
s
m
a
c
o
n
c
e
n
t
r
a
t
i
o
n
(
G
-
C
S
F
)
[
n
g
/
m
L
]
u n t r e a t e d
P o ly m e r - o n ly s . c .
8 m g m A b X s o lu t io n s . c .
1 m g m A b X - M S P s s . c .
8 m g m A b X - M S P s s . c .
Mean values are shown ± SD
Long-Acting Injectable Microparticle Formulation for a Monoclonal Antibody
47
48. SynBiosys®-based Long Acting Injectables under Development
Long-Acting Injectable Microparticle Formulations
48
Indication Drug molecule Formulation type RoA
Ocular disease Protein Microparticle Intravitreal
Sexual dysfunction Protein Microparticle SubQ
Ischemic heart disease IGF-1 / HGF Microparticle Intra-arterial
Diabetes GLP-1 analogue Microparticle SubQ
Cancer
Monoclonal
antibody
Microparticle SubQ / IM
Prostate cancer Goserelin Solid implant SubQ
Cancer Peptide Microparticle SubQ / IM
Osteoarthritis Protein Microparticle Intra-articular
Schizophrenia Small molecule Microparticle SubQ / IM
Long-Acting Injectable Microparticle Formulations
49. Long-Acting Injectable Microparticle Formulations
49
The typical technical data above serve to generally characterize the excipient. These values are not
meant as specifications and they do not have binding character. The product specification is available
separately at: www.merckmillipore.com
We provide information and advice to our customers on application technologies and regulatory matters
to the best of our knowledge and ability, but without obligation or liability. Existing laws and regulations
are to be observed in all cases by our customers. This also applies in respect to any rights of third
parties. Our information and advice do not relieve our customers of their own responsibility for checking
the suitability of our products for the envisaged purpose.
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