FENTANYL

NOVEL DRUG
Acio, Theresa
Agtarap, Sheryza
Nugal, Mikee
Pascua, Christian
Suguitan, Jastine Layrene
BA PHARMACY III- A

HISTORY OF FENTANYL
Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly
formed Janssen Pharmaceutical in 1959. In the 1960s, fentanyl was introduced as an intravenous
anesthetic under the trade name of Sublimaze. In the mid-1990s, Janssen Pharmaceuticals
developed and introduced into clinical trials the Duragesic patch, which is a formation of an inert
alcohol gel infused with select fentanyl doses which are worn to provide constant administration
of the opioid over a period of 48 to 72 hours. After a set of successful clinical trials, Duragesic
fentanyl patches were introduced into the medical practice.
Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was
introduced under the brand name of Actiq, becoming the first quick-acting formation of fentanyl
for use with chronic breakthrough pain. More recently, fentanyl has been developed into an
effervescent tab for buccal absorption much like the Actiq lollipop, followed by a buccal spray
device for fast-acting relief and other delivery methods currently in development.
A new fentanyl product has been approved by the FDA for breakthrough cancer pain
called Onsolis. It uses a new drug delivery technology called BEMA (fentanyl buccal soluble
film) which is placed in the mouth on a small disc. There appears to be less abuse potential
because the drug cannot be crushed up and snorted like other fentanyl products.
BACKGROUND OF THE DISEASE

The study of cancer, called oncology is the work of countless doctors and scientists
around the world whose discoveries in anatomy, physiology, chemistry, epidemiology, and other
related fields made oncology what it is today. Technological advances and the ever-increasing
understanding of cancer make this field one of the most rapidly evolving areas of modern
medicine.
Cancer begins when cells in a part of the body start to grow out of control. There are
many kinds of cancer, but they all start because of out-of-control growth of abnormal cells.
Cancer is the second leading cause of death in the United States. About one-half of all men
andone-third of all women in the US will develop cancer during their lifetimes. Today, millions
ofpeople are living with cancer or have had cancer.
Human beings and other animals have had cancer throughout recorded history. So its no
surprise that from the dawn of history people have written about cancer. Some of the earliest
evidence of cancer is found among fossilized bone tumors, human mummies in ancient Egypt,
and ancient manuscripts. Growths suggestive of the bone cancer called osteosarcoma have been
seen in mummies. Bony skull destruction as seen in cancer of the head and neck has been found,
too.
Our oldest description of cancer (although the word cancer was not used) was discovered in
Egypt and dates back to about 3000 BC. Its called the Edwin Smith Papyrus and is a copy of
part of an ancient Egyptian textbook on trauma surgery. It describes 8 cases of tumors or ulcers
of the breast that were removed by cauterization with a tool called the fire drill. The writing says
about the
disease, There is no treatment.
Cancer incidence and mortality statistics reported by the American Cancer Society 1 and
other resources were used to create the list. To qualify as a common cancer for the list, the
estimated annual incidence for 2016 had to be 40,000 cases or more.
The most common type of cancer on the list is breast cancer, with more than 249,000 new cases
expected in the United States in 2016. The next most common cancers are lung cancer
and prostate cancer.
Because colon and rectal cancers are often referred to as "colorectal cancers," these two
cancer types are combined for the list. For 2016, the estimated number of new cases of colon
cancer and rectal cancer are 95,270 and 39,220, respectively, adding to a total of 134,490 new
cases of colorectal cancer.
The following table gives the estimated numbers of new cases and deaths for each common
cancer type:
Cancer Type
Estimated New Cases
Bladder
76,960
Breast (Female Male)
246,660 2,600
Colon and Rectal (Combined)
134,490
Endometrial
60,050
Kidney (Renal Cell and Renal 62,700

Estimated Deaths
16,390
40,450 440
49,190
10,470
14,240

Pelvis) Cancer
Leukemia (All Types)
Lung (Including Bronchus)
Melanoma
Non-Hodgkin Lymphoma
Pancreatic
Prostate
Thyroid

60,140
224,390
76,380
72,580
53,070
180,890
64,300

24,400
158,080
10,130
20,150
41,780
26,120
1,980

DRUG DELIVERY SYSTEM

Buccal patches or films consists of two laminates, with an aqueous solution of the
adhesive polymer being cast onto an impermeable backing sheet, which is then cut into the
required oval shape. A novel mucosal adhesive film called Zilactin - consisting of an alcoholic
solution of Hydroxy propyl cellulose (HPC) and three organic acids. The film which is applied to
the oral mucosal can be retained in place for at least 12 hrs even when it is challenged with
fluids.
Buccal Dosage form can be of:
1. Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive,
and additives mixed together.
2. Reservoir type: The buccal patch designed in a reservoir system contains a cavity for the drug
and additives separate from the adhesive. An impermeable backing is applied to control the
direction of drug delivery; to reduce patch deformation and disintegration while in the mouth;
and to prevent drug loss.
Buccal absorption: Buccal absorption leads systemic or local action via buccal mucosa.
Mechanism of buccal absorption: Buccal drug absorption occurs by passive diffusion of the
non-ionized species, a process governed primarily by a concentration gradient, through the
intercellular spaces of the epithelium. The passive transport of non-ionic species across the lipid
membrane of the buccal cavity is the primary transport mechanism. The buccal mucosa has been
said to be a lipoidal barrier to the passage of drugs, as is the case with many other mucosal
membrane and the more lipophilic the drug molecule, the more readily it is absorbed. The
dynamics of buccal absorption of drugs could be adequately described by first order rate process.
Several potential barriers to buccal drug absorption have been identified.
Factors affecting buccal absorption: The oral cavity is a complex environment for drug
delivery as there are many interdependent and independent factors which reduce the absorbable
concentration at the site of absorption.
1. Membrane Factors: This involves degree of keratinization, surface area available for
absorption, mucus layer of salivary pellicle, intercellular lipids of epithelium, basement
membrane and lamina propria. In addition, the absorptive membrane thickness, blood supply/
lymph drainage, cell renewal and enzyme content will all contribute to reducing the rate and
amount of drug entering the systemic circulation.
2. Environmental Factors:
a. Saliva: The thin film of saliva coats throughout the lining of buccal mucosa and is called
salivary pellicle or film. The thickness of salivary film is 0.07 to 0.10 mm. The thickness,
composition and movement of this film affect the rate of buccal absorption.

b. Salivary glands: The minor salivary glands are located in epithelial or deep epithelial region
of buccal mucosa. They constantly secrete mucus on surface of buccal mucosa. Although, mucus
helps to retain mucoadhesive dosage forms, it is potential barrier to drug penetration.
c. Movement of buccal tissues: Buccal region of oral cavity shows less active movements. The
mucoadhesive polymers are to be incorporated to keep dosage form at buccal region for long
periods to withstand tissue movements during talking and if possible during eating food or
swallowing.
COMPOSITION OF BUCCAL PATCHES:
A. Active ingredient.
B. Polymers (adhesive layer): HEC, HPC, polyvinyl pyrrolidone(PVP), polyvinyl alcohol
(PVA), carbopol and other mucoadhesive polymers.
C. Diluents: Lactose DC is selected as diluents for its high aqueous solubility, its flavoring
characteristics, and its physico-mechanical properties, which make it suitable for direct
compression. other example : microcrystalline starch and starch.
D. Sweetening agents: Sucralose, aspartame, Mannitol, etc.
E. Flavoring agents: Menthol, vanillin, clove oil, etc.
F. Backing layer: EC etc.
G. Penetration enhancer: Cyano acrylate, etc
H. Plasticizers: PEG-100, 400, propylene glycol, etc
METHODS TO INCREASE DRUG DELIVERY VIA BUCCAL ROUTE
Absorption enhancers : Absorption enhancers have demonstrated their effectiveness in
delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal
absorption rates. These may act by a number of mechanisms, such as increasing the fluidity of
the cell membrane, extracting inters/intracellular lipids, altering cellular proteins or altering
surface mucine. The most common absorption enhancers are azone, fatty acids, bile salts and
surfactants such as sodium dodecyl sulfate. Solutions/gels of chitosan were also found to
promote the transport of mannitol and fluorescent-labelled dextrans across a tissue culture model
of the buccal epithelium while Glyceryl mono oleates were reported to enhance peptide
absorption by a co-transport mechanism.
Advantages of buccoadhesive drug delivery:
1. Drug is easily administered and extinction of therapy in emergency can be facilitated.
2. Drug release for prolonged period of time.
3. In unconscious and trauma patients drug can be administered.
4. Drugs bypass first pass metabolism so increases bioavailability.
5. Some drugs that are unstable in acidic environment of stomach can be administered by buccal
delivery. 6. Drug absorption by the passive diffusion.
7. Flexibility in physical state, shape, size and surface.
8. Maximized absorption rate due to close contact with the absorbing membrane.
9. Rapid onset of action.
Limitations of buccoadhesive drug delivery:
1. Drugs which are unstable at buccal pH cannot be administered.
2. Drugs which have a bitter taste or unpleasant taste or an obnoxious odor or irritate the mucosa
cannot be administered by this route.
3. Drug required with small dose can only be administered.
4. Those drugs which are absorbed by passive diffusion can only be administered by this route.
5. Eating and drinking may become restricted.

Other Advantages:
Improved patient compliance due to the elimination of associated pain with injections;
administration of drugs in unconscious or incapacitated patients; convenience of
administration as compared to injections or oral medications
Sustained drug delivery
A relatively rapid onset of action can be achieved relative to the oral route, and the
formulation can be removed if therapy is required to be discontinued
Increase ease of drug administration
Though less permeable than the sublingual area, the buccal mucosa is well vascularized
and drugs can be rapidly absorbed in the venous system underneath the oral mucosa
Transmucosal systems exhibit faster initiation and decline of delivery than do transdermal
patches
Transmucosal delivery occurs is fewer variables bet. patients, resulting in lower
intersubject variability as compared to transdermal patches
The large contact surface of the oral cavity contributes to rapid and extensive drug
absorption.
Other Limitaions:
For local action the rapid elimination of drugs due to the flushing action of saliva or the
ingestion of foods stuffs may lead to the requirement for frequent dosing
The non-uniform distribution of drugs within saliva on release a solid or semi-solid
delivery system could mean that some areas of oral cavity may not receive effective
levels
For both local and systemic action, patient acceptability in terms of taste, irritacy and
mouth feel is an issue
Once place at site of absorption the patch should not be disturbed
Eating and drinking are restricted until complete absorption has taken place
The drug is administered to the inner lining of the cheek where the BioErodible
MucoAdhesive (BEMA) technology allows the polymer film to dissolve inside the
mouth.
A Supplemental New Drug Application (sNDA) for a novel formulation of the
drug Onsolis (fentanyl buccal soluble film), has been approved by the FDA . Onsolis is
manufactured by BioDelivery Sciences International (BDSI), and is used to treat
breakthrough pain in cancer patients who are tolerant to opioids . The sNDA was
submitted to the FDA after the reformulation of the pharmaceutical. The drug is
administered to the inner lining of the cheek where the BioErodible MucoAdhesive
(BEMA) technology allows the polymer film to dissolve inside the mouth. Fentanyl, an
opioid agonist, is the active ingredient in Onsolis. To prevent abuse and overdose of
fentanyl a Schedule II controlled substance the Transmucosal Immediate Release
Fentanyl (TIRF) Risk Evaluation and Mitigations Strategy (REMS) program is the only
available way to prescribe Onsolis. The FDA requires that before patients receive
treatment with Onsolis, they understand the associated risks and benefits and are able to

make an informed decision. Earlier this year, marketing authorization for Onsolis was
returned to BDSI from its revenue-sharing partner in the drug, Media Pharmaceuticals.
The company pursued marketing authorization for the drug in the US, Canada and
Mexico. BioDelivery Sciences, is bringing back to market a novel product for the
treatment of breakthrough cancer pain in opioid tolerant patients using the companys
buccal film technology, BioErodible MucoAdhesive (BEMA), said Al Medwar, vice
president, marketing and corporate development for BioDelivery Sciences International,
Inc. Onsolis is the only product that allows for simple administration by placing the film
on the inside of the cheek where it adheres and subsequently dissolves. Onsolis can only
be prescribed to patients 18 years and older who experience breakthrough pain associated
with cancer. These patients must be receiving at least 60 mg of oral morphine per day
or an equivalent dose of another opioid and continuing to experience breakthrough
pain, indicating opioid tolerance. Clinical trials of Onsolis identified the most common
side effects of the drug which include nausea, vomiting, dehydration, asthenia, dyspnea,
and fatigue. As with all opioids, the most serious reactions associated with Onsolis
include respiratory depression, circulatory depression, hypotension, and shock.

DOSAGE FORM
1.
Fentanyl injection (IM/IV)
Brand Name: Sublimaze
Advantages:
used for reducing pain before, during, or after a surgical operation
also used for treating severe pain unrelated to surgery
No first pass effect takes place
In IV, Absorption is not required

Disadvantages:
In IV, Sepsis-Infection and phlebitis might occur, drug injected cannot be retrieved

In IM, painful, dependent on blood flow

Fentanyl skin patch

Brand Name: Duragesic
Advantages:
provide constant administration of the opioid over a period of 48 to 72 hours
Systemic effect
Specific dose contained on patch

2.

Disadvantages:
May irritate the skin
Absorption of dose may be effected by skin condition and circulation

3.

Accidental exposure to a new or used patch (either by getting it on the skin or in the
mouth) may cause serious and sometimes fatal side effects, especially in children.
If the application site and the surrounding area are exposed to direct sources of heat
(such as heating pads, electric blankets, heat lamps, saunas, hot tubs, or heated
waterbeds) the heat may cause more medicine to be released into the skin and could
cause serious, even fatal, side effects.
Fentanyl nasal spray
Brand Name: Lazanda
Advantages:
bioavailability is about 70-90%
low rate of side effects and has a promising pain reducing effect (demonstrated in
a prospective observational study in around 900 out-of-hospital patients)

Rapid absorption takes place

Rapid onset of action takes place

has minimum side effects.

No first pass effect takes place.

method in using is easy.

Disadvantages:
Irritation of the respiratory tract may take place.

4.

Fentanyl lozenges
Brand Name: Actiq
Advantages:
the first quick-acting formation of fentanyl for use with chronic breakthrough pain
bioavailability is 50% when used correctly (25% via the mouth mucosa and 25%
via the gut)

The handle allows patients to remove the agent from the mouth if they experience
signs of excessive opioid effects.

Disadvantages:
not applicable for those people with dry mouth
5.

Fentanyl buccal/sublingual tablet

Brand Name: Abstral (sublingual), Fentora (buccal),
Advantages:
Good in emergencies
Absorbed directly into the blood
Disadvantages:

6.

7.

May irritate the lining of the mouth

Easy to swallow and convert to oral medication
Needs compliance in accepting dose difficult in children and some
developmentally delayed adults

Fentanyl oral spray

Brand Name: Subsys
Advantages:
A buccal spray device for fast-acting relief
Fentanyl buccal soluble film
Brand Name: Onsolis
Advantages:
also used for chronic pain patients who have developed a tolerance to less potent
drugs such as morphine or who cannot take them due to their adverse effects.
Appears to be less abuse potential because it cannot be crushed up and snorted
like other fentanyl products
Disadvantages:
available only through a restricted distribution program, called the FOCUS
Program

SIMILAR CHARACTERISTICS:
- Can be harmful or fatal if taken by children, patients for whom it has not been prescribed,
or patients who are not tolerant to narcotic (opioid) pain medicine
- Not for short-term pain (including headache, migraine, or dental pain) or for pain that
occurs after surgery or injuries.
- A given amount of fentanyl has about 100 times the potency of the same amount of
morphine
- Often reserved for so-called breakthrough pain - a sudden, temporary increases in pain
that does not respond to the patient's usual pain treatment. This often happens in people
with ongoing pain caused by cancer.
- Not to be used in opioid-nave patients, or in those with severe respiratory depression or
severe obstructive lung conditions
- Long-term use of fentanyl patch during pregnancy may cause dependence in the unborn
baby. This can lead to withdrawal in the newborn, which can be life-threatening.
- can produce drug dependence of the morphine type and therefore has the potential for
being abused
- Abruptly stopping the drug in patients who have been taking the drug for a long time can
precipitate
a
withdrawal
reaction.
Symptoms
of
withdrawal
include nausea, diarrhea,coughing, tearing, nasal discharge, profuse sweating, twitching
muscles, and yawning.

Can cause respiratory depression (decreased rate or depth of breathing), muscle rigidity,
and reduced heart rate.
Combining fentanyl with drugs that reduce activity of liver enzymes that breakdown
fentanyl (for example, ritonavir, ketoconazole, itraconazole), may result in an increase in
fentanyl blood levels, increasing or prolonging side effects of fentanyl
Can slow breathing in newborn infants whose mothers were exposed to fentanyl
When used for long periods of time or at high doses, fentanyl may not work as well and
may require higher doses to obtain the same effect as when first taken

DOSAGE FORM (IN COMPARISON TO CONVENTIONAL THERAPY TO TREAT

CANCER)
1. Fentanyl buccal patch

Advantages:
A given amount of fentanyl has about 100 times the potency of the same amount of
morphine
Often reserved for so-called breakthrough pain - a sudden, temporary increases in pain
that does not respond to the patient's usual pain treatment. This often happens in people
with ongoing pain caused by cancer.
Is also used for chronic pain patients who have developed a tolerance to less potent drugs
such as morphine or who cannot take them due to their adverse effects.
causes pain relief much more quickly than morphine, but its effects do not last as long
Disadvantages:
Does not occur in nature
Not for short-term pain (including headache, migraine, or dental pain) or for pain that
occurs after surgery or injuries.
Has many side effects, including:
Drowsiness.
Lightheadedness.
Weakness and fatigue.
Feelings of elation (euphoria).
Dry mouth.
Difficulty urinating.
Difficulty breathing.
Constipation, which may be severe.
Skin reactions, such as irritation, itching, or hives.

2. Morphine injection

COMMON BRAND NAME(S): Duramorph, Infumorph

GENERIC NAME(S): MORPHINE SULFATE
Advantages:
Naturally occurring opioid substance, or opiate, derived from opium poppy plants
Used for ongoing pain relief in patients suffering chronic pain
Causes feelings of detachment and euphoria, which are very useful in the management of
anxiety in palliative care
Disadvantages:
Nausea and vomiting are the frequent adverse effects
May cause withdrawal reactions, especially if it has been used regularly for a long time or
in high doses. In such cases, withdrawal symptoms (such as restlessness, watery eyes,
widened pupils, sweating, runny nose) may occur if you suddenly stop using this
medication.

HOW BUCCAL SOLUBLE FILM WORKS?

Onsolis (fentanyl buccal soluble film) is an oral transmucosal form of the potent opioid
analgesic, fentanyl citrate, intended for application to the buccal mucosa. Onsolis uses the
BioErodible MucoAdhesive (BEMA) bilayer delivery technology which is comprised of
water-soluble polymeric films. Onsolis consists of a printed white bioadhesive layer bonded onto
a white inactive layer. The active ingredient, fentanyl citrate, is incorporated into the bioadhesive
layer, which adheres to the moist buccal mucosa. The amount of fentanyl delivered
transmucosally is proportional to the film surface area. It is believed that the inactive layer
isolates the bioadhesive layer from the saliva, which may optimize delivery of fentanyl across
the buccal mucosa.
CONCLUSION
In the past few decades, research in buccal drug delivery has revealed remarkable growth
and advances. The transmucosal route is becoming more and more popular because it is having
significant advantages like avoidance of first pass metabolism in the liver and pre-systemic
elimination in the gastrointestinal tract. Despite the advantages of delivering drugs through
buccal mucosa, this route is still very challenging, with the main obstacles being the limited
absorption area and the barrier properties of mucosa. The strategies studied to overcome such
obstacles include use of materials that combine mucoadhesive, penetration enhancer properties
and the design of novel formulations, which besides improving patient compliance favour in
intimate and prolonged contact of the drug with the absorption mucosa. New and unforeseen
challenges are expected in the use of mucoadhesive for the delivery of new drugs and in the
search of ideal mucoadhesives.