RECENT INNOVATIONS INSTERILE DOSAGE FORMS

Content Content 1. What are sterile dosage forms.

2. Types of Conventional Sterile dosage forms.

3. What is the need to develop an innovative sterile dosage forms.

4. Types of sterile dosage form,4.1 Ophthalmic.4.2 Intranasal & Pulmonary Drug Delivery.4.3 Implants.4.4 Parenteral.4.5 Others.

5. References

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1. What are sterile dosage forms A dosage form is said to be sterile

when it is free from,o Microrganism,o Pathogens ando Spores

In short must be free from all types of Microbial contamination.

Sterile products are mostly injected, applied onto eye and administer intranasally.

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3. What is the need to develop an innovative sterile dosage forms

OphthalmicOphthalmicPulmonary Pulmonary

Drug DeliveryDrug DeliveryImplantsImplants ParenteralParenteral

To reduce frequency of administration

To enhance bioavailability

To target the deliveryOf drugs

To maintain stabilityTo control the release

Of potent drugsTo reduce side effects

Hence enhance patientcompliance

So reduce frequency Of administration

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4. Types of sterile dosage form

3.1 Ophthalmic3.2 Intranasal &

Pulmonary Drug Delivery

3.3 Implants 3.4 Parenteral 3.5 Others

RadiopharmaceuticalsSolution for

irrigationSurgical Medicinal Devices

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4.1 Ophthalmic

4.1.1 Ophthalmic Insitu gels

4.1.2 Ophthalmic Cationic emulsion

4.1.3 Ophthalmic Iontophoresis

4.1.4 Ophthalmic Nanoparticle

4.1.5 Ophthalmic Discosomes

4.1.6 Ocular Inserts

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4.1.1 Ophthalmic Insitu gels These type of systems can be formulated as drug-containing liquids suitable for

administration by instillation into the eye, which upon exposure to physiological conditions will shift to the gel (semi-solid) phase, thus increasing the precorneal residence time and enhancing the ocular bioavailability of the drug.

Mechanism by which Insitu gels are being formed in eye are,1. Temperature Dependent System2. pH dependent system3. Ion Induced System

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4.1.2 Ophthalmic Cationic emulsion

They are developed by the Novagali pharmaceuticals for ophthalmic applications in retina via the trans-scleral route

Electrostatic attraction that occurs between positively charge droplets and negatively charged cell membranes.

Administration onto the eye has shown, increase the residence time of the drug at cornea, with a lower contact angle and an increased spreading coefficient in comparison with conventional eye drops and anionic emulsions.

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4.1.3 Ophthalmic Iontophoresis Iontophoresis is an active method of

drug delivery which uses a small electrical current to transport ionized drugs into and through body tissues.

The results of studies in rabbit, demonstrate that iontophoresis offers a noninvasive and reproducible means of delivering a model anionic drug to eye tissues, specifically to the retina.

These studies serve as the basis for future clinical studies aimed at delivering therapeutic drugs to the back of the eye for treatment of ocular diseases, such as Age-related macular degeneration (AMD) and diabetic retinopathy (DR).

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4.1.4 Ophthalmic NanoparticleSrno Drug Problem with

conventional dosage form

Type Polymer Method of preparation

Effect Advantage of Nanoparticle over conventional

1. Carteolol Side effect Nanoparticle &

Nanocapsule

Poly episilon caprolactone

Drug was entrapped in a oily core of carrier

Cardiovascular effect found to decline

2. Acyclovir Low bioavailability

Nanospheres

Poly-d-l-lactic acid

Nanoprecipitation

Increase aqueous level of drug & improve pharmacokinetic profile

3. Tobramycine Low bioavailability

Retain for longer time on corneal surface

Increase bioavailability

4. Metipranolol Side effect Nanocapsule

Poly isobutyl cynoacrylate

Oil is most influencing parameter in these

Drastic reduction is side effect

5. Gencyclovir Frequency of administration

Nanospheres

Albumin & glutaraldehyde

Coacervation Covalent binding of albumin, prolongs the

residence of Nanoparticle in eye

Frequency of administration

6. Cyclosporine-A

Low bioavailability &

Frequency of administration

Nanocapsule

Poly episilon caprolactone

High corneal level (upto 5 times) Level remain higher for upto three

days

7. Ibuprofen & Indomethacin

Low bioavailability

Nanoparticle &

Nanocapsule

Poly episilon caprolactone

Submicron emulsion increases corneal penetration

High corneal level (upto 3 times)

8. Pilocarpine Frequency of administration

(6times)

Nanocapsule

Poly isobutyl cynoacrylate

Interfacial polymerizatio

n

Increase in contact time Twice daily installation

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4.1.5 Ophthalmic Discosomes Disc shaped niosomes are known as discosomes.

Discosomes, in addition to their many advantages, seem to have a special advantage towards the ocular route, wherein their large size may prevent their drainage into the systemic pool.

Furthermore, their ‘‘disc’’ shape provides for a better fit in the cul-de-sac of the eye.

Non-ionic surfactant-based discoidal noisome (discosomes) of timolol maleate have been reported to be promising systems for the controlled ocular administration of water-soluble drugs, releasing the drug in a biphasic profile.

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4.1.6 Ocular Inserts A truly continuous Zero order kinetic &

controlled release was achieved using ocusert.

Pilocarpine ocuserts ( by Alza corporation of California) i.e. pilo- 20 & pilo- 40 are examples

This device is more popular among younger patients as compared to elder population who have difficulties in insertion, do not retain device well and often do not notice if it falls out.

The major drawback for using this therapy is

1. high cost of the device 2. this system is not biodegradable, 3. required to be removed and replaced with a fresh one.

They also include soluble, bioadhesive ophthalmic inserts, prosert and mydriasert.

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S.No Drug Formulation Category Polymers / Bases

1. Pilocarpine Sol to gel Miotic agent C.A.P.

2. Pilocarpine Matrices Miotic agent HPC & PVP

3. Pilocarpine Hydrogel Miotic agentPolyacrylic acid and

Polyacrylamide

4. Dexamethasone Ocularinsert Anti-inflammatoryC.A.P.,

Eudragit RS. 100 and RL 100

5. Pilocarpine nitrate Ocularinsert Miotic agent Na hyaluronate

6. Tropicamide Ocularinsert Mydriatic agent Na hyaluronate

7. Pilocarpine nitrate Gel Miotic agent Polyacrylic acid

8. Timolol Sol to gel Anti-glaucoma agent  GelriteÒ 

9. Timolol Maleate  Ocular insert  Anti-glaucoma agent (PVME - MA) 

10. Methyl Prednisolone  Microspheres  Anti-inflammatory Na hyaluronate 

11. Penicillin G  Liposomes Antibiotic Phospholipids

12. Timolol maleate  In-situ forming gel Anti-glaucoma agent  HPMC and Polyacrylic acid 

13.Gentamicin, Tobramycin and

Ciprofloxacin  Iontophoresis Anti-infective agents 

                                  ---

14. Indomethacin  Nanocapsules Micro

emulsionAnti- inflammatory  Poloxamer

15. Indomethacin Nanocapsules Anti-inflammatory  Chitosan and Poly-L-Lysine

16. Ciprofloxacin   Ocular insert  Anti-infective agent  HPMC,MC,PVP 

17. Insulin Ocular devices  Anti diabetic  Gelatin sponge

18. Tropicamide Liposomes in gel.  Mydriatic agent  Polycarbophil 

19. Ketorolac Tromethamine  Ocular Inserts  Anti-inflammatory  HPMC,PVP,MC

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4.2 Pulmonary Drug Delivery

4.2.1 Liposome and Lipid Based Formulation

4.2.2 Proliposomes

4.2.3 Nanocochleates

4.2.4 Micro and Nanoparticulates DPI Compositions

4.2.5 Delivery of Proteins, Peptides and Macromolecules for Local and Systemic Delivery Using DPIs

4.2.6 Matrix formation

4.2.7 pro-drugs and pegylation

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4.2.1 Liposome and Lipid Based Formulation

Promising in sustaining the drug residence time within lung, improving therapeutic index, and delaying systemic dilution and thereby, reducing side effects and to control the extent of release.

Delivery of corticosteroid for asthma, ribonucleotides for respiratory influenza aminoglycosides (Tobramycin Sulphate, Amikacin Sulphate) and other antibiotics (Ciprofloxacin) for local pulmonary infections and cystic fibrosis has been reported using liposome technology.

In liposomal DPI formulations, drug encapsulated liposomes are homogenized, dispersed into carrier and converted into DPI by spray and / or freeze drying.

On inhalation, drug encapsulated liposome’s get rehydrated in lung and release drug over a period of time.

Fatty acid esters were incorporated in the lipid portion of liposome’s for prolonged steroid retention in the respiratory tract.

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4.2.2 Proliposomes

Biologically active component with a lipid or mixture having a phase transition temperature of below 37°C for inhalation has been described for manufacturing of proliposomes.

A DPI formulation comprising a lipid component and an active agent having a liquid phase transition temperature of less than or equal to 37°C on hydration and a liquid phase transition temperature of greater than 57°C in dry form.

On inhalation the drug spontaneously encapsulates into lipid inside lungs. The disclosed formulation is useful in treatment of anthrax infection on inhalation.

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4.2.3 Nanocochleates

Cochleates are derived from liposomes.

These are suspended in an aqueous containing two-phase polymer solution, perceiving different partition coefficient.

The liposome containing two-phase polymer solution, treated with positively charged molecules such as Ca2+ or Zn2+, forms a cochleate precipitate of a particle size less than 1 µm.

Novel lipid-based cochleate delivery system were used to achieve efficient systemic and mucosal delivery of pharmaceutical agents.

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4.2.4 Micro and Nanoparticulates DPI Compositions

Respirable particles carrying active principles or diagnostics in nanoparticle

Nanoparticulates DPI produced by mixing the nanoparticles with liquid carrier, then forming the resultant mixture into respirable particles.

The respirable particles were produced by spray-drying or freeze spray drying followed by comminution, for delivery to the lungs via DPIs.

Active principles were covalently attached, adsorbed or incorporated to nanoparticles.

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4.2.5 Delivery of Proteins, Peptides and Macromolecules for 4.2.5 Delivery of Proteins, Peptides and Macromolecules for Local and Systemic Delivery Using DPIsLocal and Systemic Delivery Using DPIs

It has been found that inhaled dry insulin powders are deposited in the alveolar regions of the lungs and rapidly absorbed through the epithelial cells of the alveolar region into blood circulation.

The insulin powder preferably comprises particles having a diameter range from 0.1 µm to 5 µm.

A patent on pulmonary malarial vaccine relates to particulate compositions comprising nanoparticulates for pulmonary delivery, which provide sustained release of antigens, preferably DNA and/or peptide and/or protein antigens has been developed.

As the aggregate particles degrade in the body, MSP-1 and AMA-1 proteins are released into the blood stimulating a humoural immune response.

The individual particles in the range of 0.1 micron are referentially phagocytosed & initiating the cellular immune response that is necessary for a complete immunity.

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PRODUCT NAME COMPANY NAME

INDICATION DEV.STATUS TECHNOLOGY DESCRIPT’N

Exubera nektar Type I and ii diabetes

Filled for approval in us and uk

Inhance DPI

morphine aradign Pain Phase ii Arex Electronic aqueous droplets

VR 004 Vectura Erectile dysfuction Phase II aspirair DPI

Leuprolide Nectar/ enzon Endometriosis Phase I Inhance DPI

Human growth factor

Alkermes/ lilly Growth hormone deficiency

Phase I AIR DPI

Alveair Coremed USA Type I and II Diabetes

Phase I Alveair Bioadhesive polymer technology

Bio air ( insulin) Biosante Preclinical CAP particles Formulation technology.

Small molecule analgesic

Direct haler A/S Pain Early research Direct haler pulmonary

DPI

Testosterone Aradigm Undisclosed NA Arex Electronic aqueous droplets

Undisclosed Chrysalis technology

Undisclosed Early research Aria Soft mist

Undisclosed Microdose Undisclosed Early research Microdose Piexo-electric aqueous droplets

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4.3 Implants

Implants are defined as sterile solid drug products made by compression, melting, or sintering. They generally consist of the drug and rate-controlling excipient.

4.3.1 Implantable Osmotic Pumps

4.3.2 Vapor pressure moderated implantable device

4.3.3 Biodegradable device

4.3.4 Ophthalmic implant

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4.3.1 Implantable Osmotic Pumps

HIGUCHI LEEPER

HIGUCHI THEEUWES

MINI OSMOTIC

PUMP

ROSE NELSON

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4.3.2 Vapor Pressure Moderated Implantable Devices

opening

Drug and Polymer Collapsible bagPropellant

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4.3.3 Biodegradable device

Example of Biodegradable device is ZOLADEX (Goserelin Acetate Implant)

Zoladex is a sterile, biodegradable product containing goserelin acetate designed for subcutaneous injection continuous release over 28 days.

Zoladex is also availble as Zoladex- 3 month. The base consists of a matrix of D, L- lactic and glycolic acid copolymer.

Zoladex is indicated for a number of disorders, including palliative treatment of advanced carcinoma of the prostate. It is also used in treatment of advanced breast cancer.

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Cont… Another Example of Biodegradable device is Gliadel Wafer Implant

Gliadel Wafer (polifeprosan 20 with carmustine implant) is indicated in newly diagnosed patients with high-grade malignant as an adjunct to surgery and radiation.

After a neurosurgeon removes a high-grade malignant, up to eight Gliadel Wafers can be implanted in the cavity where the tumor resided.

Once implanted, the Gliadel Wafers slowly dissolve, releasing high concentrations of BCNU into the tumor site targeting microscopic tumor cells that sometimes remain after surgery.

The specificity of Gliadel Wafer minimizes drug exposure to other areas of the body.

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4.3.4 Ophthalmic implantLACRISERT A rod shaped pellet of Hydroxypropyl

Cellulose without preservative

This device is designed as a sustained release artificial tear insert for the treatment of dry eye disorders

VITRASERT Effective in treating cytomegalovirus

(CMV) retinitis.

This implant delivers the drug directly to the retina for over 5 months.

The device was prepared by coating a ganciclovir pellet with PVA.

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4.4 Parenteral

4.4.1 Liposome Parenteral Formulation

4.4.2 Depofoam

4.4.3Microsphere

4.4.4 Noisome

4.4.5 Nanosuspension

4.4.6 Others

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4.4.1 Liposome Parenteral Formulation

AmBisome is amphotericin B liposome for injection.

It is a sterile, nonpyrogenic lyophilized product for intravenous infusion.

Intravenous infusion forms upon reconstituted with sterile water for injection.

AmBisome is a true single bilayer liposomal drug delivery system, consisting of unilamellar bilayer liposomes with amphotericin B intercalated within the membrane.

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Cont…DaunoXomeDaunoXome

DaunoXome (DaunoXome (daunorubicin citrate daunorubicin citrate liposome injectionliposome injection) is a sterile, pyrogen-) is a sterile, pyrogen-free, preservative-free product in a single free, preservative-free product in a single use vial for intravenous infusion. use vial for intravenous infusion.

DaunoXome is a liposomal preparation of DaunoXome is a liposomal preparation of daunorubicin formulated to maximize the daunorubicin formulated to maximize the selectivity of daunorubicin for solid selectivity of daunorubicin for solid tumors tumors in situ. in situ.

DoxilDoxil

Doxil (Doxil (doxorubicin HCl liposome doxorubicin HCl liposome injectioninjection) is doxorubicin ) is doxorubicin hydrochloride (HCl) encapsulated hydrochloride (HCl) encapsulated in STEALTHin STEALTH®® liposomes for liposomes for intravenous administration.intravenous administration.

The STEALTH liposomes of The STEALTH liposomes of DoxilDoxil are are formulated with surface-formulated with surface-bound methoxypolyethylene bound methoxypolyethylene glycolglycol (MPEG), a process often (MPEG), a process often referred to asreferred to as pegylation pegylation, to , to protectprotect liposomes liposomes from detection from detection by the mononuclear phagocyte by the mononuclear phagocyte system (MPS)system (MPS) and to and to increase increase blood circulation timeblood circulation time..

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4.4.2 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.

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DepoDur

There is widespread recognition that relief of post-operative pain is sub-optimal.

In DepoDur™ (previously known as DepoMorphine™), our DepoFoam™ sustained-release injectable technology maintains therapeutically effective levels of morphine for 48 hours (the period of peak post-operative pain) from a single epidural injection given before or during the procedure.

DepoDur™ eliminates the need for an indwelling catheter and infusion pumps.

DepoCyt

DepoCyt is first sustained-release injectable product to reach the market which uses DepoFoam technology.

DepoCyt cuts the injection frequency to every second week, allowing treatment on an outpatient.

DepoCyt® was launched in the USA in May 1999.

Cont…

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4.4.3 4.4.3 Microsphere 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.

The Biosphere® drug delivery system offers:

1. Gentle manufacturing process, preserving protein integrity and stability

2. Biocompatible and biodegradable materials

3. Good control of properties providing long-term release profiles

4. Injections via small needles or needle-less systems

5. High encapsulation efficiency, minimising loss of costly drug substance

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4.4.4 Niosome The success achieved with liposomes stimulated the search for other

vesicle forming amphiphiles which led to the development of Niosomes.

Non-ionic surfactants were among the first alternative materials studied.

Drug targeting of anticancer drugs like methotrexate and doxorubicin has been achieved by niosomal formulations.

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4.4.5 Nanosuspension

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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

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4.4.6 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

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.

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.

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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

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4.5. Others

4.5.1 Prefilled-Syringe

4.5.2 Pens

4.5.3 Auto injector

4.5.4 Infusion Pump

4.5.5 Ultrasafe Passive Delivery System

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4.5.1 Prefilled-Syringe Duoject - Prefillable Syringe

Systems And Lyophilized Drug Reconstitution Devices: its work on the advancement of parenteral technology, developing medical devices for pharmaceutical clients which meet patient needs for safety, precision and simple ease of use in drug reconstitution and delivery

Vari-vial™ Prefillable Syringe: Vari-Vial™ - a prefillable syringe and novel bottomless vial capable of being processed on standard 'in-house or outsourced' vial production machinery.

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4.5.2 Pens Insulin Pens: Insulin pen is the

combination of the syringe and insulin cartridge into one.

It has made multiple insulin injections more convenient, portable and acceptable.

Disposable And Semi-disposable Injection Pens: Patented disposable 'dose memory' pens and 'click-on' pen needles make giving injections more convenient

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4.5.3 Auto injector EpiPen and EpiPen autoinjectors: Epipen autoinjectors are designed as

emergency supportive therapy for allergenic reactions (anaphylaxis) and are not a replacement or substitute for immediate medical or hospital care.

Disposable And Reusable Auto-injectors: Disposable and reusable auto-injector platforms provide safe and easy injections from pre-filled syringes.

PEN INJECTORS - TYPICAL DOSING RANGE 0.01ML-0.8MLPen injectors are typically multi-dose injectors used mainly for frequent injections. Injection pens are used with dedicated drug cartridges and pen needles.

REUSABLE INJECTION PENSYpsomed reusable injection pens are available with easy to read electronic displays for multiple dosing with optimal accuracy.

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4.5.4 Infusion Pump Insulin Pumps: The insulin pump is a small portable device (about the size and weight of

a pager) that delivers insulin continuously through a fine plastic tube into a site under the skin. Users will need to go through a comprehensive training.

The insulin pump generally gives you better control and more meal flexibility but is costly and still requires frequent blood sugar monitoring.

The catheter at the end of the insulin pump is inserted through a needle into the abdominal fat of a person with diabetes.

Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner.

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Cont…Cont… Infusion Pumps: COLLEAGUE CX Infusion Pump with GUARDIAN Feature. From simple

infusions to medication therapies requiring complex dose calculations.

GUARDIAN feature to help reduce medication errors by alerting staff when programmed doses are not met within institutional limits

PCA II Pump Innovative in Pain Management: The convenience of safe and precise Patient Controlled Analgesia in a flexible system designed with advanced technology. This is progressive, innovative, and effective pain management in a sophisticated, yet simple-to-operate, instrument.

FLO-GARD 6201 Volumetric Infusion Pump and the FLO-GARD 6301 Dual-Channel Volumetric Infusion Pump: Flow Check Occlusion Alarm offers an in-line resistance display of incremental back pressure. Flow Rate Calculation is automatic after volume and time are selected.

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4.5.5 Ultrasafe Passive Delivery System

The UltraSafe® Passive™ Delivery System offers a complete pharmaceutical delivery system as well as an effective solution for protecting workers from the horror of needlesticks.

Specifically designed for pre-filled glass syringes, the UltraSafe® Passive™ Delivery System leaves nothing to change. With innovative passive protection that delivers the ultimate in sharps injury protection and safety, it provides a complete delivery system with no change in current technique.

UltraSafe® needle guards are designed to attach easily to most pre-filled glass syringes commonly used with vaccines, low molecular weight heparins and many new biotechnology drugs.

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5. References1. http://www.pharmaceutical-technology .com/contractors/drug_delivery/crossject/2. http://www.pharmaceutical-technology.com/contractors/drug_delivery/syringes/3. http://www.ondrugdelivery.com/publications/Pre-Injectables%20lo%20res.pdf4. http://www.pharmainfo.net/exclusive/reviews/advances_in_ophthalmic_drug_delivery_systems_-_part_ii./5. http://www.pharmainfo.net/exclusive/reviews/advances_in_ophthalmic_drug_delivery_systems_:_part_i/6. http://www.azonano.com/Details.asp?ArticleID=15387. http://www.amphastar.com/products.htm8. http://www.drugs.com/PDR/Pulmicort_Respules.html9. http://www.astrazeneca-us.com/pi/pulmicortrespules.pdf10. http://wistechnology.com/article.php?id=118611. http://www.freedommedical.com/hosp.asp?mode=sel&pid=00024&intpage=2&action=<<12. http://www.ioltech.com/beta/uk/pharma.html13. http://www.surgical-net-tv.com/lab-ioltech.cfm14. http://www.insitevision.com/wt/page/index15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15547470&dopt=Abstract16. http://www.advantagerx.com/dispins.htm 17. http://www.run500miles.com/insulin_pumps.htm18. http://www.nipro.co.jp/english/profile/labo.html19. http://www.gilead.com/wt/sec/liposomal_technology20. http://www.ambisome.com/21. http://www.drugs.com/PDR/Doxil_Injection.html22. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=6223. http://www.pjonline.com/Editorial/19990904/education/parenteral2.html 24. http://www.nlm.nih.gov/medlineplus/ency/imagepages/18035.htm25. http://www.pjbpubs.com/uploads/drugdelivery.pdf26. Ansel’s Pharmaceutical Dosage Forms and Drug delivery Systems. Eighth edition. Novel Dosage Forms and Drug Delivery Technologies: 652-

672.

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