Transcript INNOVATIVE STERILES

RECENT INNOVATIONS IN
STERILE DOSAGE FORMS
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
4.2
4.3
4.4
4.5
Ophthalmic.
Intranasal & Pulmonary Drug Delivery.
Implants.
Parenteral.
Others.
5.
References
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1. What are sterile dosage forms

o
o
o
A dosage form is said to be sterile
when it is free from,
Microrganism,
Pathogens and
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
Pulmonary
Drug Delivery
Ophthalmic
To reduce frequency
of administration
To enhance
bioavailability
Hence enhance patient
compliance
Implants
Parenteral
To target the delivery
To reduce side effects
To maintain stability
Of drugs
To control
the release
Of potent drugs
So reduce frequency
Of administration
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4. Types of sterile dosage form
3.1 Ophthalmic
3.2 Intranasal &
Pulmonary
Drug Delivery
3.3 Implants
3.4 Parenteral
Radiopharmaceuticals
3.5 Others
Solution for
irrigation
Surgical
Medicinal Devices
5 / 45
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,
Temperature Dependent System
pH dependent system
Ion Induced System
1.
2.
3.
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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 Nanoparticle
Srno
Drug
Problem with
conventional
dosage form
Type
Polymer
1.
Carteolol
Side effect
Nanoparti
cle &
Nanocaps
ule
Poly episilon
caprolactone
2.
Acyclovir
Low
bioavailability
Nanospher
es
Poly-d-l-lactic
acid
3.
Tobramycine
Low
bioavailability
4.
Metipranolol
Side effect
Nanocaps
ule
Poly isobutyl
cynoacrylate
5.
Gencyclovir
Frequency of
administration
Nanospher
es
Albumin &
glutaraldehyde
6.
CyclosporineA
Low
bioavailability &
Frequency of
administration
Nanocaps
ule
Poly episilon
caprolactone
7.
Ibuprofen &
Indomethacin
Low
bioavailability
Nanoparti
cle &
Nanocaps
ule
Poly episilon
caprolactone
8.
Pilocarpine
Frequency of
administration
(6times)
Nanocaps
ule
Poly isobutyl
cynoacrylate
Method of
preparation
Effect
Advantage of Nanoparticle over
conventional
Drug was entrapped in a oily
core of carrier
Cardiovascular effect found to
decline
Nanoprecipitat
ion
Coacervation
Increase aqueous level of drug &
improve pharmacokinetic profile
Retain for longer time on
corneal surface
Increase bioavailability
Oil is most influencing
parameter in these
Drastic reduction is side effect
Covalent binding of
albumin, prolongs the
residence of Nanoparticle in
eye
Frequency of administration
High corneal level (upto 5 times)
Level remain higher for upto three
days
Interfacial
polymerizatio
n
Submicron emulsion
increases corneal penetration
High corneal level (upto 3 times)
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
this system is not biodegradable,
required to be removed and replaced with a fresh one.
2.
3.

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 agent
Polyacrylic acid and
Polyacrylamide
4.
Dexamethasone
Ocularinsert
Anti-inflammatory
C.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
emulsion
Anti- 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
Local 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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DEV.STATUS
TECHNOLOGY
DESCRIPT’N
Filled for approval
in us and uk
Inhance
DPI
Pain
Phase ii
Arex
Electronic
aqueous droplets
Vectura
Erectile dysfuction
Phase II
aspirair
DPI
Nectar/ enzon
Endometriosis
Phase I
Inhance
DPI
Alkermes/ lilly
Growth
hormone
deficiency
Phase I
AIR
DPI
Alveair
Coremed USA
Type I
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
pulmonary
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
PRODUCT NAME
COMPANY
NAME
INDICATION
Exubera
nektar
Type
I
diabetes
morphine
aradign
VR 004
Leuprolide
Human
factor
growth
and
and
ii
II
haler
DPI
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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
ROSE
NELSON
HIGUCHI
LEEPER
MINI
OSMOTIC
PUMP
HIGUCHI
THEEUWES
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4.3.2 Vapor Pressure Moderated
Implantable Devices
opening
Drug and Polymer
Collapsible bag
Propellant
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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.
24 / 45
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.
25 / 45
4.3.4 Ophthalmic implant
LACRISERT

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.
28/ 45
Cont…
DaunoXome

DaunoXome (daunorubicin citrate
liposome injection) is a sterile, pyrogenfree, preservative-free product in a single
use vial for intravenous infusion.

DaunoXome is a liposomal preparation of
daunorubicin formulated to maximize the
selectivity of daunorubicin for solid
tumors in situ.
Doxil

Doxil (doxorubicin HCl liposome
injection) is doxorubicin
hydrochloride (HCl) encapsulated
in STEALTH® liposomes for
intravenous administration.

The STEALTH liposomes of
Doxil are formulated with surfacebound methoxypolyethylene
glycol (MPEG), a process often
referred to as pegylation, to
protect liposomes from detection
by the mononuclear phagocyte
system (MPS) and to increase
blood circulation time.
29 / 45
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.
30 / 45
Cont…
DepoDur

There is widespread recognition that relief of
post-operative pain is sub-optimal.

In DepoDur™ (previously known as
DepoMorphine™), our DepoFoam™ sustainedrelease 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.
31 / 45
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:
Gentle manufacturing process, preserving
protein integrity and stability
Biocompatible and biodegradable
materials
Good control of properties providing longterm release profiles
Injections via small needles or needle-less
systems
High encapsulation efficiency, minimising
loss of costly drug substance
1.
2.
3.
4.
5.
32 / 45
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
cavities
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
molecules
with
defined
Drug targeting
35/ 45
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 cigarlike cochleate.
36 / 45
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
37 / 45
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
38 / 45
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.
39 / 45
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
40 / 45
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 autoinjector platforms provide safe and easy injections from pre-filled syringes.

PEN INJECTORS - TYPICAL DOSING RANGE 0.01ML-0.8ML
Pen injectors are typically multi-dose injectors used mainly for frequent
injections. Injection pens are used with dedicated drug cartridges and pen
needles.
REUSABLE INJECTION PENS
Ypsomed reusable injection pens are available with easy to read electronic
displays for multiple dosing with optimal accuracy.

41 / 45
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.
42 / 45
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-tooperate, 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.
43 / 45
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.
44/ 45
5. References
1.
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25.
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