Recent Innovation in Parenterals

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RECENT INNOVATIONS IN PARENTERALS:

RECENT INNOVATIONS IN PARENTERALS Abhishek Bagadiya DEPARTMENT OF PHARMACEUTICS Atmiya Institute of Pharmacy Rajkot-360 005 Abhishek Bagadiya Recent innovations in parentrals 1 /93

Content :

Content What are Parenterals ? Types of Conventional Parenteral Dosage Forms. What is the need to develop Parenteral Dosage Form? Innovations in Parenterals References Questions Abhishek Bagadiya Recent innovations in parentrals 2 /93

What are Parenterals? :

What are Parenterals ? Parenterals : para : outside & enteron : intestine It denotes route of administration other than oral route They are Sterile, Pyrogen free preparations injected through skin and mucous membrane into internal body compartment Abhishek Bagadiya Recent innovations in parentrals 3 /93

Conventional Parenteral Dosage Products :

Injections Powders for injections or infusions Cefuroxime injection Gels for injections Colloidal solution Iron dextran Injectable emulsion Propofol USP Injectable suspension Methyl Prednisolone acetate Oily injection Dimercaprol Conventional Parenteral Dosage Products Abhishek Bagadiya Recent innovations in parentrals 4 /93

Conventional Parenteral Dosage Products :

Conventional Parenteral Dosage Products Infusions Admixtures consist of one or more sterile drug products added to an IV fluid. IV fluids: Dextrose , Sodium chloride, Water , Ringer solutions Electrolyte preparation: Sodium chloride Dialysate : It contains Dextrose & electrolyte, which removes the harmful substances by osmosis and diffusion (Used in patients with disorder as renal failure, poisoning, and electrolyte disturbances & In peritoneal dialysis) Abhishek Bagadiya Recent innovations in parentrals 5 /93

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5. Irrigating solutions Not intended for infusion into the venous system. Topical administration Used in irrigating wounds, moistening dressings, and cleaning surgical instruments Infusion of irrigating solutions Surgeons performing urological procedure often use irrigating solution to perfuse tissues in order to maintain the integrity of surgical field, remove blood, and provide a clear field of view Concentrates for injections or infusions Abhishek Bagadiya Recent innovations in parentrals 6 /93

What is the need to develop an innovative PARENTRAL dosage forms? :

What is the need to develop an innovative PARENTRAL dosage forms? Abhishek Bagadiya Recent innovations in parentrals 7 /93

Innovations in Parenterals:

Innovations in Parenterals Depot system Implants Liposome Parenteral Formulation Depofoam Niosomes Microspheres Nanosuspension Multiple Emulsion Resealed Erythrocytes Abhishek Bagadiya Recent innovations in parentrals 8 /93

Depo System: SABER™ Depot Injection Technology:

Depo System: SABER™ Depot Injection Technology The SABER Delivery System is an injectable , biodegradable delivery system that uses a high viscosity carrier such as sucrose acetate isobutyrate (SAIB) and one or more pharmaceutically acceptable additives Abhishek Bagadiya Recent innovations in parentrals 9 /93

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The drug to be delivered by the SABER Delivery System is dissolved or dispersed in a SABER system for subsequent injection. Upon injection, the SABER system forms a depot from which the drug is delivered at a controlled rate over periods of a few days to 3 months or more. Both water soluble and insoluble drugs of small and large molecules can be formulated, sterilized and released from SABER depot injection systems Abhishek Bagadiya Recent innovations in parentrals 10 /93

Advantages:

Advantages 1. HIGH DRUG PAYLOAD Higher doses and smaller injection volumes than typical polymer based formulations 2. PEPTIDE/ PROTEIN DELIVERY SABER formulations isolate peptides & proteins in a non-aqueous non-polymeric solution to prevent premature exposure to water, which can lead to better drug stability & help minimize burst while modulating release over long periods of time Abhishek Bagadiya Recent innovations in parentrals 11 /93

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3. EASE OF ADMINISTRATION Small needle gauges, small injection volumes and low solution viscosity result in easier, less painful administration 4. EASE OF MANUFACTURE Compared to microspheres and other polymer-based systems,SABER is readily manufacturable at low cost using standard equipment & processes for small volume parenteral injections Abhishek Bagadiya Recent innovations in parentrals 12 /93

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5. PATENT PROTECTION Strong Patent Protection. DURECT has a strong intellectual property position covering SABER, SABER-like materials, and various applications of this technology to pharmaceuticals, biotechnology and drug delivery Abhishek Bagadiya Recent innovations in parentrals 13 /93

Examples of SABER in use POSIDUR™:

Examples of SABER in use POSIDUR™ Abhishek Bagadiya Recent innovations in parentrals 14 /93 Post-operative pain relief depot, POSIDUR, is a sustained-release injectable using our SABER system to deliver bupivacaine , an off-patent anesthetic agent. POSIDUR is designed to be administered to a surgical site at the time of surgery for post-operative pain relief and is intended to provide local analgesia for up to 3 days, which we believe coincides with the time period of the greatest need for post surgical pain control in most patients Posidur is in Phase III clinical trials in the U.S.,and Phase II in Europe

Implants:

Implants They were defined as small rod shaped or ovoid shaped . sterile tablets consisting of the highly purified drug, usually compressed without excipient . Intended for subcutaneous implantation in body tissue The devices thus prepared had a high degree of hardness and virtually zero porosity. since water did not penetrate the matrix, drug release occurred principally by surface dissolution Abhishek Bagadiya Recent innovations in parentrals 15 /93

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Abhishek Bagadiya Recent innovations in parentrals 16 /93

Advantages of Implants :

Advantages of Implants 1. Potential for controlled release Implants are available which deliver drugs by zero-order controlled release kinetics. Zero order controlled release offers the advantages of: Avoiding the peaks (risk of toxicity) and troughs (risk of ineffectiveness) of conventional therapy Reducing  the dosing frequency Increasing patient compliance Abhishek Bagadiya Recent innovations in parentrals 17 /93

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2. Potential for intermittent release Externally programmable pumps can facilitate intermittent release. Intermittent release can facilitate drug release in response to such factors as : Circadian rhythms Fluctuating metabolic needs The pulsatile release of many peptides and proteins Abhishek Bagadiya Recent innovations in parentrals 18 /93

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3 . Potential for bio-responsive release Bio-responsive release from implants is an area of ongoing research 4. Improved drug delivery By avoiding first pass effect Abhishek Bagadiya Recent innovations in parentrals 19 /93

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5. Flexibility Considerable flexibility is possible with these systems, in the choice of materials, methods of manufacture, degree of drug loading, drug release rate  etc. Abhishek Bagadiya Recent innovations in parentrals 20 /93

ZOLADEX (goseraline acetate implant):

ZOLADEX ( goseraline acetate implant) Zoladex is a sterile, biodegradable product containing goseralin acetate designed for sub cutaneous injection, continuous release for 28 days Zoladex is also available as zoladex-3 months. The base consists of a matrix of D,L- lactic & glycolic acid copolymer. It is indicated for no. of disorders, including palliative treatment of advanced carcinoma of prostrate Abhishek Bagadiya Recent innovations in parentrals 21 /93

Slide 22:

It is also used in the treatment of advanced breast cancer It should be stored at room temp. & should not exceed 25 o C Abhishek Bagadiya Recent innovations in parentrals 22 /93

Zoladex safe system syringe:

Zoladex safe system syringe The advanced design of the Zoladex safe system syringe makes it safer & convenient for the health care professional: Built in protective needle sleeve Reduces potential for needle stick injury Automatically activates upon complete plunger depression No safety clip and no added steps Preloaded to ensure precise and accurate dosing Ready to use at your convenience- no mixing, reconstitution or refrigeration necessary Abhishek Bagadiya Recent innovations in parentrals 23 /93

ATRIGEL® In Situ Implant System :

ATRIGEL ® In Situ Implant System The ATRIGEL system is a proprietary delivery system that can be used for both Parenteral and site-specific drug delivery It contains a biodegradable polymer dissolved in a biocompatible carrier When the liquid polymer system is placed in the body using conventional needles and syringes, it solidifies upon contact with aqueous body fluids to form a solid implant Abhishek Bagadiya Recent innovations in parentrals 24 /93

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Abhishek Bagadiya Recent innovations in parentrals 25 /93

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Abhishek Bagadiya Recent innovations in parentrals 26 /93

Biodegradable Polymers Used in the ATRIGEL® System:

Biodegradable Polymers Used in the ATRIGEL® System Poly(DL- lactide ) PLA Poly(DL- lactide -co- glycolide ) PLG Poly(DL- lactide -co- caprolactone ) PLC Polyanhydrides PAH Abhishek Bagadiya Recent innovations in parentrals 27 /93

Biocompatible Hydrophilic Solvents Used in the ATRIGEL® System:

Biocompatible Hydrophilic Solvents Used in the ATRIGEL ® System N-methyl-2-pyrrolidone (MVP) 2-Pyrrolidone Polyethylene glycol 400 Dimethyl sulfoxide Glycofurol Solketal Ethyl lactate Dimethylacetamide Abhishek Bagadiya Recent innovations in parentrals 28 /93

Biocompatible Hydrophobic Solvents Used in the ATRIGEL® System:

Biocompatible Hydrophobic Solvents Used in the ATRIGEL ® System Triacetin Ethyl acetate Propylene carbonate Triethyl citrate Ethyl heptanoate Benzyl alcohol (BA) Benzyl benzoate (BB) Abhishek Bagadiya Recent innovations in parentrals 29 /93

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Abhishek Bagadiya Recent innovations in parentrals 30 /93

Biodegradable Tri-Block Copolymers of PEG &PLGA :

Biodegradable Tri-Block Copolymers of PEG &PLGA Abhishek Bagadiya Recent innovations in parentrals 31 /93 Injectable liquid formulations of degradable polymers + drug that entrap the drug as they gel at body temperature

Slide 32:

If a drug is incorporated into the polymer solution, it becomes entrapped within the polymer matrix as it solidifies, and is slowly released as the polymer biodegrades Abhishek Bagadiya Recent innovations in parentrals 32 /93

Advantages of ATRIGEL® :

Advantages of ATRIGEL ® The ATRIGEL ® system may provide benefits over traditional drug alternatives such as tablets, capsules, injections and continuous infusion Pharmaceuticals may be blended into this liquid delivery system at the time of manufacturing or may be added later by the physician at the time of use Abhishek Bagadiya Recent innovations in parentrals 33 /93

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1.COMPATIBLE Depending on the patient's medical needs, system delivers water soluble and insoluble compounds high & low molecular weight compounds including peptides and proteins 2.EASE OF INJECTION The ATRIGEL ® liquid formulation uses standard needles for ease of administration Abhishek Bagadiya Recent innovations in parentrals 34 /93

Slide 35:

3. SUSTAINED DRUG RELEASE Released over a specified period of time, from a few days to several months, thereby reducing the frequency of drug administration 4. BIODEGRADABLE The ATRIGEL ® implant is fully biodegradable and therefore does not require removal prior to the next injection Abhishek Bagadiya Recent innovations in parentrals 35 /93

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5.BIOCOMPATIBLE All components of the ATRIGEL ® system are biocompatible and each has established safety and toxicity profiles 6.SITE-SPECIFIC DRUG DELIVERY Drugs are administered directly to the target area, potentially achieving higher drug conc. at the desired site of action and thereby minimizing systemic side effects Abhishek Bagadiya Recent innovations in parentrals 36 /93

Applications of ATRIGEL® Implant Syatem:

Applications of ATRIGEL ® Implant Syatem ATRIGEL ® can deliver a wide range of therapeutics including: Small molecules Peptides Proteins Vaccines Natural products Abhishek Bagadiya Recent innovations in parentrals 37 /93

Marketed Products:

Marketed Products Eligard ® product : prostate cancer Eligard is a sustained-release formulation of leuprolide acetate, a luteinizing hormone-releasing hormone (LHRH) agonist, designed to reduce the amount of testosterone in the body. Eligard is available as one-, three-, four- and six-month dosageforms . Abhishek Bagadiya Recent innovations in parentrals 38 /93

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Atridox ® , for the treatment of periodontal disease Abhishek Bagadiya Recent innovations in parentrals 39 /93

Manufacturer:

Manufacturer QLT USA Partners with QLT Pfizer Inc. Sanofi-aventis Group Several other non-exclusive, non-disclosed partnerships Abhishek Bagadiya Recent innovations in parentrals 40 /93

DURIN™ Biodegradable Implants:

DURIN™ Biodegradable Implants The DURIN biodegradable implant technology is a platform for parenteral delivery of drugs for periods of weeks to six months or more. The technology is based on the use of biodegradable polyester excipients , which have a proven record of safety and effectiveness in approved drug delivery and medical device products Abhishek Bagadiya Recent innovations in parentrals 41 /93

Slide 42:

In addition to polymer engineering, the physical structure of DURIN implants is designed to achieve the desired therapeutic outcome. The overall form of the implant is typically a small rod or pellet that can be placed by means of a needle or trochar . The composition of the rod or pellet can be monolithic, where the drug is uniformly dispersed throughout the excipient . Abhishek Bagadiya Recent innovations in parentrals 42 /93

Slide 43:

Alternatively,designs are also possible in which the rod or pellet is composed of a drug-rich core surrounded by a rate-controlling membrane. Depending on drug chemistry and desired kinetics, the membrane may or may not contain drug. Typically, the drug and excipient are mixed together, and the mixture is formed into a fiber , rod, tablet, or pellet by an extrusion or molding process. Abhishek Bagadiya Recent innovations in parentrals 43 /93

Slide 44:

The ratecontrolling membrane, if required, may be applied during or subsequent to the core-forming process. The release of the drug from the implant can occur by degradation of the excipient , diffusion of the drug through the excipient or pores in the excipient , or a combination of degradation and diffusion. Abhishek Bagadiya Recent innovations in parentrals 44 /93

Slide 45:

The relative contributions of these processes and the overall release profile are controlled by a number of variables including drug content, excipient composition, and implant design. As a result, a variety of drug delivery profiles including first-order, zero-order, delayed, and biphasic drug release can all be achieved with the DURIN implant technology Abhishek Bagadiya Recent innovations in parentrals 45 /93

Advantages of DURIN™ :

Advantages of DURIN™ 1. SUPERIOR DELIVERY KINETICS Compared to microspheres or in situ gel forming depots, DURIN implants offer release kinetics that are closer to zero order, with essentially no initial burst following administration 2. FULLY BIODEGRADABLE DURIN implants degrade by hydrolysis after drug release and are fully absorbed by body tissues. Hence, a surgical intervention to remove the device is not required Abhishek Bagadiya Recent innovations in parentrals 46 /93

Slide 47:

3. FLEXIBILITY DURIN implants can deliver a wide variety of drugs including hydrophobic and hydrophilic compounds as well as small and large molecules. Our proprietary implant design allows for first order, zero-order, delayed or biphasic drug release profiles. Durations can range from weeks to six months or more Abhishek Bagadiya Recent innovations in parentrals 47 /93

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4.SUPERIOR DRUG LOADING & STABILITY DURIN implants can be manufactured with very high drug loading (up to 70-80%) making extremely small implants feasible. DURIN implants are ideal for long term delivery because, within the implant, drug exists in solid form which enhances drug stability. Abhishek Bagadiya Recent innovations in parentrals 48 /93

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5. HISTORY OF SAFE HUMAN USE DURIN implants are manufactured using lactide glycolide co-polymers (biodegradable, biocompatible polymer excipients ) that have a long history of safe human use in medical devices and drug implants. 6. COST EFFECTIVE Unlike microspheres and other implants, the DURIN technology is readily scaled to large production volumes in a cost effective manner Abhishek Bagadiya Recent innovations in parentrals 49 /93

Manufacturer:

Manufacturer Abhishek Bagadiya Recent innovations in parentrals 50 /93 DURECT Corporation

Liposome Parenteral Formulation :

Liposome Parenteral Formulation Liposomes are concentric bilayer vesicles in which aqueous volume is entirely enclosed by a membraneous lipid bilayer mainly composed of natural or synthetic phospholipids Abhishek Bagadiya Recent innovations in parentrals 51 /93

The commonly used phospholipids :

The commonly used phospholipids Naturally occurring phospholipids: 1. Phopshatidylcholine (PC) 2. Phosphotidylethanol amine (PE) 3. Phosphotidylserine (PS) Synthethic phospholipids: 1. Dioleoylphosphatidylcholine (DOPC) 2. Distearoylphosphatidylcholine (DSPC) 3. Dioleoylphosphatidylethanolamine (DOPC) 4. Distearoylphosphatidylethanolamine (DSPE) Abhishek Bagadiya Recent innovations in parentrals 52 /93

Cholesterol :

Cholesterol The purpose of adding cholesterol is, it functions as a fluidity buffer i.e.. below the phase transition temperature it makes the membrane less ordered and increases the permeability; and above the phase transition temperature it makes the membrane more ordered and less permeable Abhishek Bagadiya Recent innovations in parentrals 53 /93

Preparation Methods of Liposomes :

Preparation Methods of Liposomes Hydration Method The lipids are dissolved in suitable organic solvent; these solvents are later removed by evaporation, vacuum drying or lyophillization . The dry lipid film/ paste or cake is then hydrated, resulting in the formation of large multilamellar vesicles; its size is reduced to the range of 100nm to 200nm,by homogenization or extrusion Abhishek Bagadiya Recent innovations in parentrals 54 /93

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Emulsion Method The solid phospholipids are dissolved in a suitable organic solvent & then added to aqueous medium with vigorous agitation, the organic solvent is removed under pressure & the resulting liposomal dispersion is homogenized These liposomes can be formulated in the form of a aerosol suspension,gel,cream or lotion or as a dry vesicular powder ( proliposomes ). Abhishek Bagadiya Recent innovations in parentrals 55 /93

Advantages of Liposome Parenteral Formulation:

Advantages of Liposome Parenteral Formulation Provide selective passive targeting to tumor tissues(liposomal doxorubicin) Increased efficacy and therapeutic index Increased stability via encapsulation Improved pharmacokinetic effects(reduced elimination, increased circulation lifetimes) Flexibility to couple with site specific ligands to achieve active targeting Abhishek Bagadiya Recent innovations in parentrals 56 /93

Disadvantages of liposomes :

Disadvantages of liposomes RES uptake Drug leakage problems Poor stability in the blood. High product cost Abhishek Bagadiya Recent innovations in parentrals 57 /93

Types of Liposmes:

Types of Liposmes Conventional liposomes Stealth liposomes Immuno - liposomes Charged liposomes Abhishek Bagadiya Recent innovations in parentrals 58 /93

Applications of Liposomal Parenteral Formulations:

Applications of Liposomal Parenteral Formulations Liposomal anticancer agent Liposomes as vaccine adjuvants Liposomal anti-infective agents Abhishek Bagadiya Recent innovations in parentrals 59 /93

Under Various Clinical Trials:

Under Various Clinical Trials Abhishek Bagadiya Recent innovations in parentrals 60 /93

Marketed Products:

Marketed Products System Drug Target disease Status Product AmBiosome Liposome IV Amphotericin B Systemic fungal infections, Visceral Leishmaniasis Approved by 18 countries including Europe, USA NeXstar,USA Amphocil Liposome IV Amphotericin B Systemic fungal infections Approved in UK, Russia, Finland, Irland , Europe SEQUUS, USA ABLC Liposome IV Amphotericin B Systemic fungal infections Approved in UK The liposome company, USA Abhishek Bagadiya Recent innovations in parentrals 61 /93

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Abhishek Bagadiya Recent innovations in parentrals 62 /93

DepoFoam:

DepoFoam ® is a non-classical liposome technology designed for sustained release of therapeutic agents following injection into sites other than the bloodstream Unlike classical liposomes , where the lipid bilayers are in concentric shells, each MLV particle is a honeycomb of numerous non-concentric aqueous chambers surrounded by lipid bilayers DepoFoam Abhishek Bagadiya Recent innovations in parentrals 63 /93

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Abhishek Bagadiya Recent innovations in parentrals 64 /93

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DepoFoam ® is a proprietary, proven drug delivery technology platform that provides highly versatile, sustained-release delivery of medications. DepoFoam technology has been successfully used in products registered in a number of territories including the United States, European Union, Australia, New Zealand, and South America ( DepoCyt ® , DepoCyte ® and DepoDur ® ) Abhishek Bagadiya Recent innovations in parentrals 65 /93

Advantages of DepoFoam® :

Advantages of DepoFoam ® Releases encapsulated drug over a desired period of time, from 1 to 30 days Without altering the current drug molecule Utilizes a ready-to-use aqueous suspension Works with narrow gauge needles and pen systems (27-31 gauge) Incorporates membrane components that are natural, well tolerated, and cleared by normal metabolic pathways Less than 3% lipid and is biodegradable & biocompatible Abhishek Bagadiya Recent innovations in parentrals 66 /93

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Offers flexible delivery that can be designed to offer an immediate release dose followed by sustained delivery Proprietary proven delivery platform Two products: worldwide registrations and supply Manufactured and developed at Pacira's cGMP facilities for over 15 years Ongoing technology enhancement programs Abhishek Bagadiya Recent innovations in parentrals 67 /93

Marketed Products:

Marketed Products DepoDur ® DepoCyt (e) ® Abhishek Bagadiya Recent innovations in parentrals 68 /93

Slide 69:

DepoDur ® (morphine sulfate extended-release liposome injection) is an extended-release, injectable formulation of morphine utilizing Pacira’s DepoFoam ® technology DepoDur is indicated for epidural administration for the treatment of pain following major surgery. DepoDur is designed to provide effective pain relief for up to 48 hours following one epidural injection and has demonstrated improved patient mobility and freedom from indwelling catheters. DepoDur was approved by the FDA in 2004 DepoDur ® Abhishek Bagadiya Recent innovations in parentrals 69 /93

DepoCyt(e)®:

DepoCyt (e) ® DepoCyt (e) ® ( cytarabine liposome injection) is a sustained-release liposomal formulation of the chemotherapeutic agent cytarabine utilizing Pacira’s DepoFoam ® technology Depocyt (e) is indicated for the intrathecal treatment of lymphomatous meningitis , a life-threatening complication of lymphoma, a cancer of the immune system DepoCyt ® was launched in the USA in May 1999 and full approval in 2007 Abhishek Bagadiya Recent innovations in parentrals 70 /93

EXPAREL™ :

EXPAREL ™ EXPAREL ™ ( bupivacaine extended-release liposome injection) is Pacira’s proprietary drug candidate consisting of bupivacaine encapsulated in DepoFoam , both of which are currently used in FDA-approved products. Bupivacaine is a well-characterized anesthetic/analgesic that has an established safety profile with more than 20 years of use in the United States Abhishek Bagadiya Recent innovations in parentrals 71 /93

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EXPAREL is designed to extend the duration of analgesia provided by the commonly used local analgesic , bupivacaine . Based on clinical trial data, EXPAREL provides continuous and extended postsurgical analgesia for up to 72 hours , compared with bupivacaine’s analgesic timeline of 7 hours or less. Pacira believes EXPAREL will address a significant unmet medical need for a long-acting non- opioid postsurgical analgesic Abhishek Bagadiya Recent innovations in parentrals 72 /93

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Pacira believes that the utilization of EXPAREL in the armamentarium of post operative analgesics may reduce the dependence on opioid use in the post operative setting and delay the time to first opioid use so that oral rather than parenteral opioids can be used. This may: Result in improved patient satisfaction and outcomes; Abhishek Bagadiya Recent innovations in parentrals 73 /93

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Minimize breakthrough episodes of pain and significantly reduce the consumption of supplemental opioid medications and; Simplify postsurgical pain management and reduce hospital cost and staff time on non-patient care, monitoring of infusion pumps, catheters, leading to improved hospital economics Abhishek Bagadiya Recent innovations in parentrals 74 /93

Niosomes:

Niosomes Niosomes are nonionic surfactant vesicles obtained on hydration of synthetic nonionic surfactants, with or without incorporation of cholesterol or others They are vesicular systems similar to liposomes Abhishek Bagadiya Recent innovations in parentrals 75 /93

Advantages over liposomes:

Advantages over liposomes Synthetic non-ionic surfactants readily available Significantly cheaper Stable in air and do not require any special handling or storage conditions (Baillie 1985) Chemically stability Precise in chemical composition Abhishek Bagadiya Recent innovations in parentrals 76 /93

Structure of Niosome:

Structure of Niosome Abhishek Bagadiya Recent innovations in parentrals 77 /93

Surfactants:

Surfactants Non ionic surfactant used, to prevent GIT irritation.The HLB value of surfactant is important Amphiphilic nature is prerequisite Examples: Abhishek Bagadiya Recent innovations in parentrals 78 /93 Alkyl and dialkyl polyglycerol ethers Dialkylpolyoxyethylene ether Alkyl galactosides Sorbiton mono oleate Steroidal oxyethylene ether Laurat ethers Castor oil. Polyoxyethylatedhydrogenated

Cholesterol:

Cholesterol Cannot form bilayers, but bring changes in fluidity and permeability to bilayers Rigid steroidal skeleton in between carbon chains will restrict free movement of carbons, thus provide absolute rigidity to bilayers Can be used in high molar concentrations 1:1 ratio is more consistent and effective Stabilise and prevent leak from vesicles Abhishek Bagadiya Recent innovations in parentrals 79 /93

Applications of Niosomal Parenteral Formulations:

Niosomes as vaccine adjuvants Niosomes at targeted site Anticancer niosomes Niosomes as diagnostic imaging Applications of Niosomal Parenteral Formulations Abhishek Bagadiya Recent innovations in parentrals 80 /93

Microspheres:

The Biosphere ® drug delivery system consists of microspheres of highly purified starch forming a matrix in which the drug is encapsulated by using a proprietary and gentle process without exposure to organic solvents, high shear forces or extremes of pH Microspheres Abhishek Bagadiya Recent innovations in parentrals 81 /93

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The Biosphere ® drug delivery system offers : Gentle manufacturing process , preserving protein integrity and stability Biocompatible and biodegradable materials Good control of properties providing long-term release profiles Injections via small needles or needle-less systems High encapsulation efficiency, minimising loss of costly drug substance Abhishek Bagadiya Recent innovations in parentrals 82 /93

Nanosuspension:

Nanosuspension Abhishek Bagadiya Recent innovations in parentrals 83 /93

Slide 84:

Sr. No. Types of Nanoparticles Material Used Applications 1. Polymeric nanoparticles Biodegradable polymers Controlled and targeted drug delivery 2. Solid lipid nanoparticles Melted lipid dispersed in an aqueous surfactant Least toxic and more stable colloidal carrier systems as alternative to polymers 3. Nanocrystals & nanosuspensions Drug powder is dispersed in a surfactant solution Stable systems for controlled delivery of poorly water soluble drugs 4. Polymeric micelles Amphiphilic block copolymers Systemic and controlled delivery of water insoluble drugs 5. Liposomes Phospholipid vesicles Controlled and targeted drug delivery 6. Dendrimers Tree like molecules with defined cavities Drug targeting 7. Magnetic NPs An inorganic core of iron oxide (magnetite) coated with polymer such as dextran Drug targeting, Diagnostic tool in biology and medicine 8. Gold nanoshells Dielectric (typically gold sulfide or silica) core and a metal (gold) shell Tumor targeting 9. Nanowires or Carbon nanotubes Metals, semiconductors or carbon Gene and DNA delivery 10. Ferrofluids Iron oxide magnetic NPs surrounded by a polymeric layer For capturing cells and other biological targets from blood or other fluids and tissue samples Abhishek Bagadiya Recent innovations in parentrals 84 /93

Others:

Transferosomes : Modified liposomes developed to increase the transdermal permeation of drug . Deformability is achieved by using surface active agent in proper ratio. Ethosome : Ethosomal system is a vesicular system composed mainly of phospholipids & alcohol (ethanol or IPA, sometimes polyols ; glycol) in relatively high concentration & water. Better membrane permeability. Discosomes Others Abhishek Bagadiya Recent innovations in parentrals 85 /93

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Virosomes : Reconstituted lipid vesicles equipped with viral glycoprotein is used for DNA transfer . Emulsomes : The emulsomes can be explicitly distinguished from fat emulsion or lipid microsphere as they are distinctively sphere vesicular graft like system due to utilization of higher quantities of PC both as emulsifying agent as well as surface modifier. Abhishek Bagadiya Recent innovations in parentrals 86 /93

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Cochleates : Cochleates are cigar-like microstructures that consist of a series of lipid bilayers which are formed as a result of the condensation of small unilamellar negatively charged liposomes . In the presence of calcium, the small phosphatidylserine (PS) liposomes fuse and form large sheets . These sheets have hydrophobic surfaces and, in order to minimize their interactions with water, tend to roll-up into the cigar-like cochleate . Abhishek Bagadiya Recent innovations in parentrals 87 /93

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Sr. no Name Drug Formulation Company 1 Rapamune Rapamycin Nanosuspension Weyth-Ayerst 2 Emend Antiemetic Nanosuspension Merck 3 Rexin-G Gene Nanosuspension Epeins Biotechnology 4 Abraxane Paclitaxel Nanosuspension American bioscience inc. 5 Alza J & J Insulin Liposomes 6 Doxil Doxorubicin Liposomes Sequus 7 Daunoxome Daunorubicin Liposomes NeXstar 8 AmBisome Amphotericin B Liposomes NeXstar Abhishek Bagadiya Recent innovations in parentrals 88 /93

References:

Vyas S.P., Targetted & Controlled Drug Delivery, 1 st Edition 2002, CBS Publishers & Disributors,New Delhi,Page No.3-458. Jain N.K., Advances in Controlled and Novel Drug Delivery, 1 st Edition 2001, CBS Publishers & Disributors,New Delhi,Page No.204-232,381-426. Loyed V. Allen, Ansel`s Pharmaceutical Dosage Forms and Drug Delivery Systems, 8 th Edition, B.I. Publication Pvt. Ltd., New Delhi, Page No.44-506, Clive Prestidge , Current Trends in Liposomal Drug Delivery System, Ian Wark Research Institute, University of South Australia, Austrlia . http://www.pharmaceutical-technology.com/contractors/drug_delivery/micro-sphere/ http://www.micro-sphere.com/templates/default/viewCat.php?pID=11 http://www.pharmainfo.net/reviews/review-pegylated-liposome-cancer-therapy-and-delivery-biomaterial [Accessed on 28th July 2010] http://www.pharmainfo.net/reviews/liposome-versatile-platform-targeted-delivery-drugs [Accessed on 28th July 2010 http://www.pharmainfo.net/pharma-student-magazine/liposomes-emerging-field-targeted-drug-delivery [Accessed on 28th July 2010] References Abhishek Bagadiya Recent innovations in parentrals 89 /93

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www.depodur.com http://www.pacira.com/products-discovery.php http://www.pharmainfo.net/kranthikumar/niosomes-drug-delivery-system http://www.pharmainfo.net/reviews/non-ionic-surfactant-based-vesicle-niosome-potential-ocular-drug-delivery-system-overview Abhishek Bagadiya Recent innovations in parentrals 90 /93

Study Questions:

Explain Depofoam technology with examples. Write note on liposomes for parenteral use. Write note on implants. Write a note on Biosphere technology. Give examples of extended action parenteral products. What is liposome?Enlist the material used for the preparation of liposome.Write any one method of preparation. Study Questions Abhishek Bagadiya Recent innovations in parentrals 91 /93

Slide 92:

Give commonly used technique for development of parenteral controlled release formulation. Discuss in detail about dissolution controlled and adsorption type formulation. Write a note on nanosuspension . Write a note on nanoparticle . Abhishek Bagadiya Recent innovations in parentrals 92 /93

Slide 93:

Thank You Abhishek Bagadiya Recent innovations in parentrals 93 /93