RECENT INNOVATIONS IN

PARENTERAL 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 Ophthalmic.
4.2 Intranasal & Pulmonary Drug Delivery.
4.3 Implants.
4.4 Parenteral.
4.5 Others.

5. References
 1. What are sterile dosage forms
 A dosage form is said to be
sterile when it is free from,
o Microrganism,
o Pathogens and
o Spores

 In short must be free from

all types of Microbial
contamination.

 Sterile products are mostly

injected, applied onto eye
and administer intranasally.
 Types of sterile dosage form

Ophthalmic Intranasal & Implants Parenteral

Pulmonary Others
Drug
Delivery

Radiopharmaceutic Solution for Medicinal

Surgical
als irrigation Devices

5 / 45
 What is the need to develop an
innovative sterile dosage forms

Pulmonary
Ophthalmic Implants Parenteral
Drug Delivery

To reduce To enhance To reduce side To maintain To control

bioavailability effects To target the stability
frequency the release
delivery
of administration Of potent
Of drugs
drugs

So reduce
frequency
Hence enhance Of
patient administration
compliance
 AmBisome
 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.
 DaunoXome

 DaunoXome (daunorubicin citrate liposome

injection) is a sterile, pyrogen-free,
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 surface-bound
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.
 DepoFoam® is a non-
classical liposome
technology designed
for sustained release
of therapeutic agents
following injection
into sites other than
the bloodstream.
Microspheres are Microspheres are
small spherical sometimes referred to as
particles, with microparticles.
diameters in the
Microspheres can be
micrometer range
manufactured from
(typically 1 μm to various natural and
1000 μm (1 mm). synthetic materials.
Nanoparticulate system
 Types of Material Used Applications
Nanoparticles
Polymeric Biodegradable polymers Controlled and targeted drug delivery
nanoparticles
Solid lipid Melted lipid dispersed in an Least toxic and more stable colloidal
nanoparticles aqueous surfactant carrier systems as alternative to polymers
Nanocrystals & Drug powder is dispersed in a Stable systems for controlled delivery of
nanosuspensions surfactant solution poorly water soluble drugs
Polymeric micelles Amphiphilic block copolymers Systemic and controlled delivery of water
insoluble drugs
Liposomes Phospholipid vesicles Controlled and targeted drug delivery
Dendrimers Tree like molecules with defined Drug targeting
cavities
Magnetic NPs An inorganic core of iron oxide Drug targeting, Diagnostic tool in biology
(magnetite) coated with polymer and medicine
such as dextran
Gold nanoshells Dielectric (typically gold sulfide Tumor targeting
or silica) core and a metal (gold)
shell
Carbon nanotubes Metals, semiconductors or carbon Gene and DNA delivery
Ferrofluids Iron oxide magnetic NPs For capturing cells and other biological
surrounded by a polymeric layer targets from blood or other fluids 35/
and 45

tissue samples
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
39 / 45
machinery.
 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
 Auto injector
 EpiPen and EpiPen autoinjectors: These 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-0.8ml
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
reusable injection pens are available with easy to read electronic
displays for multiple dosing with optimal accuracy.

41 / 45
 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
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, 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.

43 / 45
 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.

 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
 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

6 / 45
 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 System
2. pH dependent system
3. Ion Induced System

7/ 45
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.
8 / 45
 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 9 / 45
diabetic retinopathy (DR).
 4.1.4 Ophthalmic Nanoparticle
Drug Problem Type Polymer Method of Effect Advantage of
with preparation Nanoparticle over
convention conventional
al dosage
form
Carteolo Side effect Nanopa Poly Drug was Cardiovascular
l rticle & episilon entrapped in a effect found to
Nanoca caprolactone oily core of decline
psule carrier

Acyclovi Low Nanosp Poly-d-l- Nanoprecipita Increase aqueous

r bioavailabil heres lactic acid tion level of drug &
ity improve
pharmacokinetic
profile
Tobram Low Retain for Increase
ycine bioavailabil longer time on bioavailability
ity corneal surface

Metipra Side effect Nanoca Poly Oil is most Drastic reduction

nolol psule isobutyl influencing is side effect
cynoacrylate parameter in 10 / 45
these
 Drug Problem Type Polymer Method Effect Advantage of
with of Nanoparticle over
convention preparati conventional
al dosage on
form
Gencyclo Frequency Nanosp Albumin & Coacervat Covalent binding of Frequency of
vir of heres glutaraldehy ion albumin, prolongs administration
administrati de the residence of
on Nanoparticle in eye
Cyclospo Low Nanoca Poly High corneal level
rine-A bioavailabili psule episilon (upto 5 times) Level
ty & caprolactone remain higher for upto
Frequency three days
of
administrati
on
Ibuprofe Low Nanop Poly Submicron High corneal level
n& bioavailabili article episilon emulsion increases (upto 3 times)
Indomet ty & caprolactone corneal penetration
hacin Nanoca
psule
Pilocarpi Frequency Nanoca Poly Interfacial Increase in contact Twice daily installation
ne of psule isobutyl polymeriz time
administrati cynoacrylate ation
on (6times) 10 / 45
 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

eye.

 Non-ionic surfactant-based 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.
11 / 45
 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
 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.
12/ 45
S.No Drug Formulation Category Polymers / Bases
1. Pilocarpine Sol to gel Miotic agent C.A.P.
2. Pilocarpine Matrices Miotic agent HPC & PVP
Polyacrylic acid and
3. Pilocarpine Hydrogel Miotic agent
Polyacrylamide
C.A.P.,
4. Dexamethasone Ocularinsert Anti-inflammatory
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
Gentamicin, Tobramycin and
13. Iontophoresis Anti-infective agents
Ciprofloxacin ---
Nanocapsules Micro
14. Indomethacin Anti- inflammatory Poloxamer
emulsion
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 13 / 45

 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
14 / 45
 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.

15 / 45
 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.

16 / 45
 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.
17 / 45
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.

18 / 45
 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.

19 / 45
PRODUCT NAME COMPANY INDICATION DEV.STATUS TECHNOLOGY DESCRIPT’N
NAME

Exubera nektar Type I and ii Filled for approval Inhance DPI

diabetes in us and uk
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 Alkermes/ lilly Growth hormone Phase I AIR DPI

factor deficiency
Alveair Coremed USA Type I and II Phase I Alveair Bioadhesive
Diabetes polymer
technology
Bio air ( insulin) Biosante Preclinical CAP particles Formulation
technology.

Small molecule Direct haler A/S Pain Early research Direct haler DPI
analgesic pulmonary
Testosterone Aradigm Undisclosed NA Arex Electronic
aqueous droplets
Undisclosed Chrysalis Undisclosed Early research Aria Soft mist
technology
Undisclosed Microdose Undisclosed Early research Microdose Piexo-electric
aqueous droplets

20/ 45
 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

21 / 45
4.3.1 Implantable Osmotic Pumps

ROSE HIGUCHI
NELSON LEEPER

MINI
OSMOTIC HIGUCHI
PUMP THEEUWES

22 / 45
4.3.2 Vapor Pressure Moderated
Implantable Devices

opening

Drug and Polymer

Collapsible bag
Propellant

23/ 45
 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. 26 / 45