Unit 2 Novel Drug Delivery Systems B Pharmacy 7th Sem Carewell Pharma B.Pharmacy 7th Semester 2023 (2022-2023) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

BP 704T: NOVEL DRUG DELIVERY SYSTEMS (Theory)
Unit-II
Dr. Amit Kumar Nayak
Associate Professor, Department of Pharmaceutics,
Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj-757086, Odisha, INDIA
Microencapsulation
Microencapsulation is defined as a process of enclosing or enveloping solids, liquids or
even gases within second material with a continuous coating of polymeric materials yielding
microscopic particles (ranging from less than 1 micron to several hundred microns in size). In
this process, small discrete solid particles or small liquid droplets and dispersions are surrounded
and enclosed by applying thin coating for the purposes of providing environmental protection
and controlling the release characteristics or availability of coated active ingredients.
Microencapsulation process is widely employed to modify and delayed drug release form
different pharmaceutical dosage forms. The materials enclosed or enveloped within the
microcapsules are known as core materials or pay-load materials or nucleus, and the enclosing
materials are known as coating materials or wall material or shell or membrane.
Microparticles:
"Microparticles" refers to the particles having the diameter range of 1-1000 um,
irrespective of the precise exterior and/or interior structures.
Microspheres:
"Microspheres" particularly refers to the spherically shaped microparticles within the
broad category of microparticles.
Microcapsules:
"Microcapsules" refers to microparticles having a core surrounded by the coat or wall
material(s) distinctly different from that of the core or pay-load or nucleus, which may be solid,
liquid, or even gas.
Microcapsules can be classified on three types (Fig. 1): Carewell Pharma i). Mononuclear: Containing the shell around the core.
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ii). Polynuclear: Having many cores enclosed with in shell.
iii). Matrix type: Distributed homogeneously into the shell material.
Classification of Microcapsules
Mononuclear Polynuclear Matrix type
Fig. 1: Classification of microcapsules
Advantages of microencapsulation:
i). Providing environmental protection to the encapsulated active agents or core materials.
ii). Liquids and gases can be changed into solid particles in the form of microcapsules.
ii). Surface as well as colloidal characteristics of various active agents can be changed.
iv). modify and delayed drug release form different pharmaceutical dosage forms
v). Fori ulation of sustaine ontrolled release dosage forms can be done by modifying or
delaying release of encapsulated active agents or core materials.
Disadvantages of microencapsulation:
i). Expensive techniques.
ii). This causes reduction in shelf-life of hygroscopic agents.
iii). Microencapsulation coating may not be uniform and this can influence the release of
encapsulated materials.
Methods ofmicroencapsulation:
(a) Air suspension:
Microencapsulation by air suspension method consists of the dispersing of solids,
particulate core terials in a supporting air stream and the spray coating on the air suspended
particles (Fig. 2). Within the coating chamber, particulate core materials are suspended on an
upward moving air stream. The chamber design and its operating parameters influence a re
circulating flow of the particles through the coating-zone portion of the coating-chamber, where
a coating Carewell Pharma material is sprayed to the moving particles. During each pass through the coating-zone,
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the core material receives a coat and this cyclic process is repeated depending on the purpose of
microencapsulation. The supporting air stream also serves to dry the product while it is being
encapsulated. The drying rate is directly related to the temperature of the supporting air stream
used.
Feed suspension
Hot air
Spraying nozzle -- --.
Drying chamber
Core particles
Microcapsules -
Fig. 2: Air suspension method for microencapsulation
(b) Coacervation phase separation:
Microencapsulation by coacervation phase separation method consists of 3 steps:
i). Formation of 3 immiscible phases: a liquid manufacturing phase, a core material
phase and a coating material phase.
ii). Deposition of the liquid polymer coating on the core material.
ii). Rigidizing the coating usually by thermal, cross linking or desolvation techniques
to form microcapsules.
The deposition of liquid polymer coating around the interface formed between the core
material and the liquid vehicle phase (Fig. 3). In many cases, physical or chemical changes in the
coating polymer solutions can be induced so that phase separation of the polymers will occur.
Droplets of concentrated polymer solutions will form and coalesce to yield a two phase liquidliquid system. When the coating material is an immiscible polymer, it may be added directly.
Also monomers can be dissolved in the liquid vehicle phase and subsequently polymerized at
interface. Important equipments necessary for microencapsulation by coacervation phase
separation method are jacketed tanks with variable speed agitators. Carewell Pharma
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PHASE O
O
SEPARATION
omogeneous
Polymer Solution
Coacervate Droplets
Droplets
MEMBRANE
FORMATION
Polymenic
Membrane
Fig. 3: Coacervation phase separation method for microencapsulation
(c) Pan coating:
For relatively large particles, which are greater than 600 u in size, microencapsulation
can be done by pan coating method, which is being widely used in pharmaceutical industry for
the preparation of controlled release particulates. In this method, various spherical core
materials, such as nonpareil sugar seeds are coated with a variety of polymers (Fig. 4). In
practice, the coating is applied as a solution or as an atomized spray to the desired solid core
material in the coating pan. Generally, warm air is passed over the coated materials as the
coatings are being applied in the coating pans to remove the coating solvent. In some cases, the
process of final solvent removal is accomplished in the drying oven.
Inlet
Exhaust
Tablet bed
Fig. 4: Pan coating method for microencapsulation Carewell Pharma
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(d) Fluidized-bed technology
Fluidized-bed technology method for microencapsulation is used for the encapsulation of
solid core materials, including liquids absorbed into porous solids. This microencapsulation
method is expansively employed to encapsulate pharmaceuticals. Solid particles to be
encapsulated are suspended on a jet of air and afterward, are covered by a spray of liquid coating
material. The capsules are traveled to an area where their shells are solidified by cooling or
solvent vaporization. The processes of suspending, spraying, and cooling are repeated until the
attainment of the desired thickness of the capsule-wall. This is known as Wurster process when
the spray nozzle is located at the bottom of the fluidized-bed of particles.
(e) Spray drying and spray congealing:
Spray drying and spray congealing methods of microencapsulation are almost similar in
that both the methods entail the dispersion of core material in a liquefied coating agent and
spraying or introducing the core coating mixture into some environmental condition, whereby
relatively rapid solidification of the coating is influenced (Fig. 5). The main difference inbetween these two microencapsulation methods are the means by which the coating solidification
is carried out. In spray drying method, the coating solidification is influenced by the quick
evaporation of a solvent, in which the coating material is dissolved. In spray congealing method,
the coating solidification is accomplished by the thermal congealing of molten coating material
or solidifying a dissolved coating by introducing the coating core material mixture into a nonsolvent. Removal of non-solvent or solvent from the coated product is often done by sorption
extraction or evaporation.
Feed Flow Nozzle Gas Flow
Bag Filter
Two Fluid Nozzle
Exhaust Air
Cyclone
Drying
Chamber
Heater
Collection
Vessel
Feed
Fig.5: Spray drying method for microencapsulation Carewell Pharma
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Multiorific-centrifugation
Multiorific-centrifugation method for microencapsulation utilizes the centrifugal forces to
hurl a core particle trough an enveloping membrane. Various processing variables of multiorificcentrifugation method include (Gi) rotational speed of the cylinder, (ii) flow rate of the core and
coating materials, and (iii) concentration, viscosity and surface tension of the core material. The
multiorifice-centrifugal method is capable for microencapsulating liquids and solids of varied
size ranges with diverse coating materials. The encapsulated product can be supplied as slurry in
the hardening media or as dry powder.
(g) Sobvent Evaporation
Solvent evaporation method is appropriate for liquid manufacturing vehicle (O/W
emulsion), which is prepared by agitation of two immiscible liquids. The solvent evaporation
method involves dissolving microcapsule coating (polymer) in a volatile solvent, which is
immiscible with the liquid manufacturing vehicle phase. A core material (drug) to be
microencapsulated is dissolved or dispersed in the coating polymer solution. With agitation, the
core-coating material mixture is dispersed in the liquid manufacturing vehicle phase to obtain
the appropriate sized microcapsules. Agitation of system is continued until the solvent partitions
into the aqueous phase and is removed by evaporation. This process results in hardened
microcapsules. Several techniques can be used to achieve dispersion of the oil phase in the
continuous phase. The most common method is the use of a propeller style blade attached to a
variable speed motor.
Various process variables namely rate of solvent evaporation for the coating polymer(s),
temperature cycles and agitation rates influence the methods of forming dispersions. The most
important factors that should be considered for the preparation of microcapsules by solvent
evaporation method include choice of vehicle phase and solvent for the polymer coating, and
solvent recovery systems. The solvent evaporation method for microencapsulation is applicable
to a wide variety of liquid and solid core materials. The core materials may be either water
soluble or water insoluble materials. A variety of film forming polymers can be used as coatings.
(h) Polymerization: Carewell Pharma
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The polymerization method of microencapsulation is used to from protective
microcapsule coatings, in situ. The method involve the reaction of monomeric units positioned at
the interface existing in-between a core material and a continuous phase, wherein the core
material is dispersed. The continuous or core material supporting phase is usually a liquid or gas,
and therefore, the polymerization reaction occurs at the interfaces of liquid-liquid, liquid-gas,
solid-liquid, or solid-gas.
(i) Interfacial cross-linking
In interfacial cross-linking method of microencapsulation, the small bifunctional
monomer containing active hydrogen atoms is replaced by a biosourced polymer, like a protein.
When the reaction is performed at the interface of an emulsion, the acid chloride reacts with the
various functional groups of the protein, leading to the formation of a membrane. The interfacial
cross-linking method of microencapsulation is very versatile for pharmaceutical or cosmetic
applications.
Applications:
Different applications of microencapsulation are:
1. Microencapsulation can be used to formulate various sustained controlled release dosage
forms by modifying or delaying release of encapsulated active agents or core materials.
2. Microencapsulation can also be employed to formulate enteric-coated dosage forms, so
that the drugs will be selectively absorbed in the intestine rather than the stomach.
3. Gastric irritant drugs are being mnicroencapsulated to reduce the chances of gastric
irritation.
4. The taste of bitter drug candidates can be masked by employing microencapsulation
techniques.
5. Through microencapsulation, liquids and gases can be changed into solid particles in the
form of microcapsules.
6. Microencapsulation can employed to aid in the addition of oily medicines to tableted
dosage forms to overcome the problems of tacky granulations and in direct compression.
7. Microencapsulation can be used to decrease the volatility. A microencapsulated volatile
substance can be stored for longer times without any substantial evaporation. Carewell Pharma
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8. Microencapsulation provides environmental protection to the encapsulated active agents
from various environmental issues, such as light, heat, humidity, oxidation, etc.
9. The hygroscopic characteristics of many core materials can be reduced by
microencapsulation.
10. The separations of incompatible substances can be achieved by microencapsulation. For
example, pharmaceutical eutectics can be separated by microencapsulation. This is a case
where direct contact of materials brings about liquid formation. The stability
enhancement of incompatible aspirin-chlorpheniramine maleate mixture is accomplished
by microencapsulating both of them before mixing.
11. Microencapsulation is used to lessen the potential danger of toxic substance handling.
The toxicity owing to handling of herbicides, insecticides. pesticides and fumigants, etc.,
can be usefully lessened after microencapsulation.
References:
[1].Allen LV, Popovich NG, Ansel HC. Pharmaceutical Dosage Forms and Drug Delivery
Systems. Delhi, India: BI Publication; 2005.
[21.Lachman LA, Liberman HA, Kanig JL. The Theory and Practice ofIndustrial Pharmacy.
Mumbai, India: Varghese Publishing House, 1976.
3]. Benita S. Microencapsulation: Methods and Industrial applications, Marcel Dekker, Inc.,
New York, 1996.
4]. Singh MN, Hemant KS, Ram M, Shivakumar HG. Microencapsulation: A promising
technique for controlled drug delivery. Res Pharm Sci. 2010;5(2):65-77.
5]. Sachan
microencapsulation. Malaysian J Pharm Sci. 2006;4:65-81.
6].Kiyoyama S, Shiomori K, Kawano Y, Hatate Y. Preparation of microcapsules and control
of their morphology. J Microencapsulation. 2003:20:497
NK, Singh B, Rao KR. Controlled drug delivery through Carewell Pharma
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Mucosal Drug Delivery system
Recent years, the drug delivery via mucosal drug delivery system has become highly
popular. Certain drugs have lack of efficacy due to decreased bioavailability, gastrointestinal
intolerance, unpredictable and erratic absorption or pre-systemie elimination of other potential
route for administration. Various routes for mucosal drug delivery include oral, buccal, ocular,
nasal and pulmonary routes, etc.
Typically, mucosal drug delivery systems can be classified as:
. Non-attached mucosal drug delivery systems:
These systems are being formulated to be absorbed through the mucosa within the oral
cavity. Examples: Sublingual tablets, Fast dissolving tablets (Melt-in-mouth or orally
disintegrating tablets), etc.
2. Attached or immobilized mucosal drug delivery systems:
These systems are being formulated to be remained attached onto the mucosal surface by
the adhesive properties. These systems are also known as mucoadhesive systems. Examples:
Buccal drug delivery systems, rectal drug delivery systems, vaginal drug delivery, nasal drug
delivery systems systems, etc.
Different strategies have been adopted for controlled mucosal delivery and are based on:
1. Prolonging solely the duration of absorption process.
2. Developing unidirectional delivery systems
3. Preparing user-friendly mucosal delivery systems.
Bioadhesion:
The term 'bioadhesive' describes materials that bind or adhere to the biological
substrates. 'Bioadhesive' can be defined as a material that is capable of interacting with
biological material and being retained on them or holding them together for extended period of
time. 'Bioadhesion' may occur via 3 ways:
i). Bioadhesion in-between biological layers without the involvement of artificial
materials. Carewell Pharma
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ii). Cell adhesion into the culture dishes or adhesion to a variety of substances, such as
woods, metals, and other synthetic substances.
ii). Adhesion of artificial substances to the biological substrates like the adhesion of
hydrophilic polymers to skin or other soft tissues.
Mucoadhesive drug delivery systems:
Mucoadhesive drug delivery systems utilizes the property of mucoadhesion/bioadhesion of
certain polymers, which become adhesive on hydration and hence, can be used for targeting a
drug to the particular region of the body for extended period of time. The ability to maintain a
delivery system at a particular location for an extended period of time has great appeal for both
local as well as systemic drug bioavailability. Mucoadhesive drug delivery systems facilitate the
possibility of avoiding either destruction by gastrointestinal contents or hepatic first-pass
inactivation of drug.
Various mucoadhesive polymers are being used to formulate mucoadhesive drug delivery
systems. These can be broadly categorized as:
)Synthetic polymers:
(a) Cellulose derivatives: Methylcellulose (MC), Hydroxy ethylcellulose (HEC), Hydroxyl
propylcellulose (HPC), Hydroxy propyl methylcellulose (HPMC), Sodium carboxy
methyleellulose (NaCMC), etc.
(b) Poly (Acrylic acid) polymers: Carbomers, Polycarbophil.
(d) Poly vinyl alcohol (PVA).
(1) Natural polyners: Chitosan, gum tragacanth, sodium alginate, xanthan gum, locust
bean gum, gellan gum, etc.
Principles of bioadhesion /mucoadhesion:
For bioadhesion /mucoadhesion, 3 stages are involved:
i). An intimate contact in-between a bioadhesive/mucoadhesive and a membrane
either from a good wetting of the bioadhesive/mucoadhesive and a membrane or
from the swelling of bioadhesive/mucoadhesive.
ii). Penetration of the bioadhesive/mucoadhesive into the tissue takes place.
iii). Inter penetration of the chains of bioadhesives/mucoadhesives with mucous takes
place and then, low chemical bonds can settle. Carewell Pharma
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Several theories have been proposed to explain the fundamental mechanism of
bioadhesion /mucoadhesion:
i). Wetting theory: Ability of bioadhesive/mucoadhesive polymers to spread and develop
immediate attachment with the mucous membranes.
ii). Electronic theory: Attractive electrostatic forces in-between glycoprotein mucin network
and the bioadhesive/mucoadhesive polymers.
iii). Adsoption theory: Surface forces (covalent bonds, ionic bonds, hydrogen bonds, and van
der Waal's forces) resulting in chemical bonding.
iv). Diffusion theory: Physical entanglement of mucin strands and the flexible polymeric
chain.
v). Fracture theory: Analyses the maximum tensile stress developed during detachment of
mucoadhesive/bioadhesive drug delivery systems from the mucosal surfaces.
Advantages and disadvantages:
Advantages:
i). These systems allow the developing of contact in-between the dosage forms and the
mucosa (mucoadhesion/bioadhesion)
i). High drug concentration can be maintained at the absorptive surface for a prolonged
period.
ii). Dosage forms can be immobilized specifically at any part of the oral mucosa, buccal
mucosa, sublingual or gingival mucosa, etc.
Disadvantages:
i). Small mucosal surface for contact
ii). Lack of flexibility of dosage forms
ii). Difficult to achieve high drug release rates required for some drugs.
iv). Extent and frequency and frequency of attachment may cause local irritation. Carewell Pharma
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Transmucosal permeability:
The mucosal lining of the oral cavity is referred to as the oral mucosa. The oral mucosa
comprises the buccal, sublingual, gingival, palatal and labial mucosa. The unique environment of
the transmucosal route offers its potential as an effective route for the delivery of a variety of
drugs. Due to rich blood supply, higher bioavailability, Iymphatic drainage and direct access to
systemic circulation, the transmucosal route is suitable for drugs, which are generally susceptible
to acid-hydrolysis in the gastrointestinal tract or extensively metabolized in liver. In addition,
oral mucosa facilitates an advantage of retaining drug delivery systems in contact with the
absorptive mucosal surface for a longer period (i.e., mucoadhesion) and thus, optimizing the
drug concentration gradient across the mucosal membrane with the reduction of differential
pathways. Thus, the delivery of drugs through the transmucosal route has attracted particular
attention due to its potential for high patient compliance and unique physiological features.
The drugs to be administered through the transmucosal route need to be released from the
dosage forms to the effective delivery site (e.g., buccal or sublingual area) and pass through the
mucosal layers to enter the systemic circulation. Certain physiological features of the
transmucosal route play significant roles in this process, including pH, enzyme activity, fluid
volume and the permeability of oral mucosa. The secretion of saliva is also an important
determinant for the performance of transmucosal drug delivery. The main mechanisms
responsible for the penetration of various molecules include: Simple diffusion (paracellular or
transcellular), carrier-mediated diffusion, active transport, pinocytosis or endocytosis. However,
there is little research on to what extent this phenomenon affects the efficiency of oral
transmucosal delivery from different drug delivery systems and thus, further research needs to be
conducted to better understand this effect.
Drug delivery across the oral mucosal membranes is termed transmucosal drug delivery.
It can be divided into three main categories of transmucosal drug delivery based on the
characteristics of the oral cavity:
i). Sublingual delivery: Administration of drugs via the sublingual mucosa (the
membrane of the ventral surface of the tongue and the floor of the mouth) to the
systemic circulation.
ii). Buccal delivery: Administration of drugs via the buccal mucosa (the lining of the
cheek) to the systemic circulation. Carewell Pharma
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iii). Local delivery: For the treatment of conditions of the oral cavity, principally ulcers,
fungal conditions and periodontal disease, gingival disease, bacterial and fungal
infections, dental stomatitis, etc.
Formulation considerations of buccal delivery systems:
Transmucosal administration of drugs accross the buccal lining is defined as buccal drug
delivery. The mucosa of the buccal area has a large, smooth and relatively immobile surface,
which provides a large contact surface (Fig. 6). The large contact surface of the buccal mucosa
contributes to rapid and extensive drug absorption. Buccal drug delivery was first introduced by
Orabase in 1947, when gum tragacanth was mixed with dental adhesive powder to supply
penicillin to the oral mucosa. Recent years, buccal drug delivery has proven particularly useful
and offers several advantages over other drug delivery systems including: bypass of the
gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally
administered drugs that otherwise undergo hepatic first-pass metabolism; 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; increased ease of drug administration; and ready
termination of delivery by detaching the dosage form.
Oral epitlheliun
Basement membrane
Lamina propia
Submucosa
(contains blood
vessels and nerves)
Muscles
Fig. 6: Schematic diagram of buccal mucosa Carewell Pharma
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Buccal drug delivery occurs in a tissue that is more permeable than skin and is less
variable between patients, resulting in lower inter-subject variability. Because of greater mucosal
permeability, buccal drug delivery can also be used to deliver larger molecules such as low
molecular weight heparin. In addition, buccal drug delivery systems could potentially be used to
deliver drugs that exhibit poor or variable bioavailability, and bioavailability will be enhanced
for drugs that undergo significant first-pass metabolism. Because drug absorbed from the oral
cavity avoids both first-pass metabolism and enzymatic/acid degradation in the gastrointestinal
tract, buccal administration could be of value in delivering a growing number of potent peptide
and protein drug molecules. In addition, buccal delivery of such drug molecules is a promising
area for continued research with the aim of alternative non-invasive delivery.
The novel type buccal dosage forms include:
i). Buccal mucoadhesive tablets,
ii). Buccal patches and films,
ii). Semisolids (ointments and gels) and powders
Buccal mucoadhesive tablets: Buccal mucoadhesive tablets are dry dosage forms that have to be
moistened prior to placing in contact with buccal mucosa.
Buccal patches and films: Buccal patches and films consist 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 round or oval shape. These also offer advantages over creams and ointments
in that they provide a measured dose of drug to the site. Recent years, puccal patches and films
have received the greatest attention for buccal delivery of drugs. They present a greater patient
compliance compared with tablets owing to their physical flexibility that causes only minor
discomfort to the patient.
Semisolids (ointments and gels): Bioadhesive gels or ointments have less patient acceptability
than solid bioadhesive dosage forms, and most of the dosage forms are used only for localized
drug therapy within the oral cavity. Carewell Pharma
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Structure and design of buccal patches:
Buccal patches are of two types on the basis of their release characteristics:
i). Unidirectional buccal patches and
ii). Bidirectional buccal patches
Unidirectional patches release the drug only into the mucosa, while bidirectional patches
release drug in both the mucosa and the mouth.
Buccal patches are structurally of two types:
i). Matrix type: The buccal patch is designed in a matrix configuration contains drug,
adhesive, and additives mixed together (Fig. 7).
Backing layer
Drug anxl mucoalhesive mauix
Fig 7: Schematic representation of the matrix-type buccal patch design
ii). 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.
Composition ofbuccal patches:
Drugs: The selection of suitable drug for the design of buccal drug delivery systems should be
based on pharmacokinetic properties of the drugs to be administered. The drug should have
following characteristics for the designing of effective buccal patches:
a) The conventional single dose of the drug should be small.
b) The drugs having biological half-life between 2-8 h are good candidates for controlled
drug delivery.
c) Tmax of the drug shows wider-fluctuations or higher values when given orally.
d) Through oral route drug may exhibit first pass effect or pre-systemic drug elimination.
e) The drug absorption should be passive when given orally. Carewell Pharma
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) Buccal adhesive drug delivery systems with the size 1-3 cm and a daily dose of 25 mg
or less are preferable.
Polymers (adhesive layer): Bioadhesive polymers play a major role in the designing of buccal
patches. Bioadhesive polymers are from the most diverse class and they have considerable
benefits upon patient health care and treatment. These polymers enable retention of dosage form
at the buccal mucosal surface and thereby provide intimate contact between the dosage form and
the absorbing tissue. Drug release from a polymeric material takes place either by the diffusion
or by polymer degradation or by a combination of the both. Polymer degradation generally takes
place by the enzymes or hydrolysis either in the form of bulk erosion or surface erosion.
An ideal bioadhesive polymer for buccal patches should have following characteristics:
a) The polymer should be inert and compatible with the buccal environment.
b) It should allow easy incorporation of drug in to the formulation.
c)The polymer and its degradation products should be non-toxic absorbable from the
mucous layer.
d) It should adhere quickly to moist tissue surface and should possess the site specificity.
e) It should form a strong non covalent bond with the mucine or epithelial surface and
should possess sufficient mechanical strength.
f) The polymer must not decompose on storage or during the shelf life of the dosage form.
g) It must have high molecular weight and narrow distribution.
h) The polymer should be easily available in the market and economical.
i) The polymer should have good spreadability, wetting. swelling and solubility and
biodegradability properties.
j)The pH ofthe polymer should be biocompatible and should possess good viscoelastic
properties.
k) It should demonstrate local enzyme inhibition and penetration enhancement properties.
) It should demonstrate acceptable shelf life.
Backing layer: Backing layer plays a major role in the attachment of buccal patches to the mucus
membrane. The materials used as backing membrane should be inert, and impermeable to the
drug and penetration enhancer. Such impermeable membrane on buccoadhesive patches prevents Carewell Pharma
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the drug loss and offers better patient compliance. The commonly used materials in backing
membrane include water insoluble polymers such as ethylcellulose, Eudrajit RL and RS, etc.
Penetration enhancer: Substances that facilitate the permeation through buccal mucosa are
referred as permeation enhancers. Selection of the appropriate permeation enhancer and its
efficacy depends on the physicochemical properties of the drug, site of administration, nature of
the vehicle and other excipients. Permeation enhancers used for designing buccal patches must
be nonirritant and have a reversible effect. The epithelium should recover its barrier properties
after the drug has been absorbed. The most common classes of buccal penetration enhancers
include fatty acids that act by disrupting intercellular lipid packing, surfactants, bile salts, and
alcohols.
Plasticizers: To impart appropriate plasticity of the buccal patches, suitable plasticizers are
required to add in the formulation of buccal patches. Typically, the plasticizers are used in the
concentration of 0-20 % w/w of dry polymer. Plasticizer is an important ingredient of the film,
which improves the flexibility of the film and reduces the bitterness of the film by reducing the
glass transition temperature of the film. The selection of plasticizer depends upon the
compatibility with the polymer and type of solvent employed in the casting of film. Plasticizers
should be carefully selected because improper use of the plasticizers affects the mechanical
properties of the film. Widely used plasticizers in buccal patches and films are PEG100, 400,
propylene glycol, glycerol, castor oil etc.
Taste masking agents: Taste masking agents or taste masking methods should be used in the
formulation if the drugs have bitter taste, as the bitter drugs makes the formulation unpalatable,
especially for pediatric preparations. Thus, before incorporating the drugs in the buccal patches,
the taste needs to be masked. Various methods can be used to improve the palatability of the
formulation, such as complexation technology, salting out technology, etc. Carewell Pharma
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Mechanism of buccal absorption:
Buccal absorption leads systemic or local action via the buccal mucosa and it 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 lipophillic the drug molecule, the more readily it is
absorbed.
Factors affecting buccal absorption:
The oral cavity is a complex environment for drug delivery as there are many
interdependent as well as 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 wil 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 0.07-0.10 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.
Manufacturing methods of buccal patches
Manufacturing processes involved in making buccal patches, are namely solvent casting,
hot melt extrusion and direct milling.
1. Solvent casting: In this method, all patch excipients including the drug co-dispersed in an
organic solvent and coated onto a sheet of release liner. After solvent evaporation a thin Carewell Pharma
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layer of the protective backing material is laminated onto the sheet of coated release liner
to form a laminate that is die-cut to form patches of the desired size and geometry.
2. Hot melt extrusion: In hot melt extrusion blend of pharmaceutical ingredients is molten
and then forced through an orifice to yield a more homogeneous material in different
shapes such as granules, tablets, or films. Hot melt extrusion has been used for the
manufacture of controlled release matrix tablets, pellets and granules, as well as oral
disintegrating films. However, only a hand full article has reported the use of hot melt
extrusion for manufacturing mucoadhesive buccal patches.
3. Direct milling: In this, patches are manufactured without the use of solvents. Drug and
excipients are mechanically mixed by direct milling or by kneading, usually without the
presence of any liquids. After the mixing process, the resultant material is rolled on a
release liner until the desired thickness is achieved. The backing material is then
laminated as previously described. While there are only minor or even no differences in
patch performance between patches fabricated by the two processes, the solvent-free
process is preferred because there is no possibility of residual solvents and no associated
solvent-related health issues.
Advantages of buccal drug delivery systems
(a) Sustained drug delivery.
(b) Increased ease of drug administration.
(c)Excellentaccessibility.
(d) Drug absorption through the passive diffusion.
(e) Low enzymatic activity, suitability for drugs or excipients that mildly and reversibly
damages or irritates the mucosa, painless administration, easy drug withdrawal, facility to
include permeation.
() Versatility in designing as multidirectional or unidirectional release systems for local or
systemic actions, etc.
(g) The drug is protected from degradation due to pH and digestive enzymes of the middle
gastrointestinal tract.
(h) Improved patient compliance. Carewell Pharma
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(i) 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.
G) Flexibility in physical state, shape, size and surface.
(k) Though less permeable than the sublingual area, the buccal mucosa is well vascularized,
and drugs from the buccal systems can be rapidly absorbed into the venous system
underneath the oral mucosa.
(1) Transmucosal delivery occurs is fewer variables between patients, resulting in lower
inter-subject variability as conmpared to transdermal patches.
Limitations ofbuccal drug delivery systems:
Depending on whether local or systemic action is required the challenges faced while
delivering drug via buccal drug delivery can be enumerated as follows:
(a) 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.
(b) The non-uniform distribution of drugs within saliva on release from a solid or
semisolid delivery system could mean that some areas of the oral cavity may not
receive effective levels.
(c) For both local and systenmic action, patient acceptability in terms of taste, irritancy
and 'mouth feel' is an issue.
References:
[1].Chien YW. Novel Drug Delivery Systems, 2nd Ed, New York: Marcel Dekker Inc.:
New York, 2007.
[2].Jain NK. Controlled and Novel Drug Delivery, 1st edition, published by CBS
Publishers and Distributors, New Delhi. 1997.
(3].Gilles P, Ghazali FA, Rathbone J. Systemic oral mucosal drug delivery systems and
delivery systems, in: Rathbone M.J. (ed.), Oral Mucosal Drug Delivery, Vol. 74,
Marcel Dekker Inc, New York, 1996, pp. 241-285.
[4]. Kamath KR, Park K. Mucosal adhesive preparations, In: Swarbrick J, Boylan JC
(eds)., Encyclopedia of Pharmaceutical Technology, vol. 10., Marcel Dekker, New
York: 1994, pp. 133-163.
I5].Mathiowitz E, Chickering D, Jacob JS, Santos C. Bioadhesive drug delivery systems.
In: Mathiowitz E(ed), Encyclopedia of Controlled Drug Delivery, vol.1. Wiley, New
York, 1999, pp. 9-44.
[6]. Boylan JC. Drug delivery buccal route. In: James Swarbrick, editor. Encyclopedia of
Pharmaceutical Technology: Supplement 3, Marcel Dekker Inc 2001, pp. 800-811.
[7].Ahuja A, Khar RK, Ali J. Mucoadhesive drug delivery systems. Drug Dev Ind Pharm,
1997; 23 (5): 489-515. Carewell Pharma
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[8].Hunt G, Kearney P, Kellaway IW. Mucoadhesive polymers in drug delivery systems.
In: Johnson P, Lloyed-Jones JG (sds), Drug Delivery System: Fundamental and
Techniqes. Elis Horwood, Chichester, 1987, pp. 180.
191. Woodley J. Bioadhesion: New Possibilities for Drug Administration. Clin
Pharmacokinet, 2001; 40(2): 77-84.
[10]. Gandhi RB, Robinson JR. Oral cavity as a site for bioadhesive drug delivery,
Adv. Drug Del. Rev. 1994; 13: 43-74.
[11]. Siegel IA. Permeability of the oral mucosa, In: Meyer J. The Structure and
Function of Oral Mucosa, New York: Pergamon Press, 1984, pp. 95-108. Carewell Pharma
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Implantable Drug Delivery Systems
Implantable drug delivery systems allow targeted and localized drug delivery and may
achieve a therapeutic effect with lower concentrations of drugs. As a result, they may minimize
potential side-effects of therapy, while offering the opportunity for increased patient compliance.
This type of system also has the potential to deliver drugs which would normally be unsuitable
orally, because it avoids first pass metabolism and chemical degradation in the stomach and
intestine, thus, increasing bioavailability.
An ideal implantable parenteral system should possess following properties:
1. Environmentally stable: Implantable systems should not breakdown under the influence of
light, air, moisture, heat, etc.
2. Biostable: Implantable systems should not undergo physicochemical degredation when in
contact with biofluids (or drugs).
3. Biocompatible.: Implantable systems should neither stimulate immune response (otherwise
the implant will be rejected) nor thrombosis and fibrosis formation.
4. Removal: Implantable systems should be removability when required.
5. Non-toxic or non-carcinogenic: The degradation products or leached additives should be
completely safe.
6. Implantable systems should have minimum surface area, smooth texture and structural
characteristics similar to the tissue in which it is to be implanted to avoid irritation.
7. Implantable systems should release drugs at a constant predetermined rate for a
predetermined period.
Advantages and disadvantages:
Advantages:
1. More effective and more prolonged action.
2. Better control over drug release
3. A significantly small dose is sufficient.
Disadvantages:
1. Invasive therapyy
2. Chances of device failure Carewell Pharma
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3. Limited to potent drugs
4. Biocompatibility issues
Concept of implants:
Implants for drug delivery are several types:
1. In situ forming implants (In situ depot forming systems):
(a) In situ precipitating implants:
These implants are formed from drug containing in a biocompatible solvent. The polymer
solution form implants after subcutaneous (s.c.) or intramuscular (i.m.) injection and contact with
aqueous body fluids via the precipitation of polymers. In situ precipitating implants are
formulated to overcome some problems associated to the uses of biodegradable microparticles:
i). Requirement for the reconstitution before injection
ii). Inability to remove the dose one injected.
iii). Relatively complicated manufacturing procedures to produce a sterile, stable and
reproducible product.
(b) In situ microparticle implants:
This type of implants is formed to overcome the disadvantages associated with in situ
precipitating implants. These are:
i). High injection force.
ii). Local irritation at the injection site.
ii). Variability in the solidification rates.
iv). Irregular shape of the implants formed depending on the cavity into which the implants
are introduced (implanted).
v). Undesirable high initial burst release of drugs.
vi). Potential solvent toxicity.
These in situ implantable systems consist of internal phase (drug-containing polymer
solution or suspension) and a continuous phase (aqueous solution with a surfactant, oil phase
with viscosity enhancer and emulsifier). The two phases are separately stored in dual-chambered
syringes and mixed through a connector before administration. Carewell Pharma
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2. Solid implants:
Solid implants are generally cylindrical monolithic devices implanted by a minor surgical
incision or injected via a large bore needle into the s.c. or i.m. tissues. Subcutaneous (s.c.) tissue
is an ideal location because of its easy access to implantation, poor infusion, slower drug
absorption and low reactivity towards foreign materials.
In these implants, drugs may be dissolved, dispersed or embedded in a matrix of
polymers or waxes/lipids that control the releasing via dissolution and/or diffusion, bioerosion,
biodegradation, or an activation process, such as hydrolysis or osmosis. These systems are
generally prepared as implantable flexible/rigid molded or extruded rods, spherical pellets, or
compressed tablets. Polymers used are silicone, polymethacrylates, elastomers,
polycaprolactones, polylactide-co-glycolide, etc., whereas waxes include glyceryl monostearate.
Drugs generally presented in such implantable systems are contraceptives, naltrexone, etc.
3. Infusion devices:
Infusion devices are intrinsically powered to release the drugs at a zero order rate and the
drug reservoir can be replenished from time to time. Depending upon the mechanism by which
these implantable pumps are power to release the drugs. These are 3 types:
i). Osmotic pressure activated drug delivery systems
ii). Vapor pressure activated drug delivery systems
iii). Battery powered drug delivery systems.
Osmotic pumps:
Osmotic pumps are designed mainly by a semi-permeable membrane that surrounds a
drug reservoir (Fig. 8). The membrane should have an orifice that will allow drug release.
Osmotic gradients will allow a steady inflow of fluid within the implant. This process will lead
to an increase in the pressure within the implant that will force drug release trough the orifice.
This design allows constant drug release (zero order kinetics). This type of device allows a
favorable release rate but the drug loading is limited.
The historical development of osmotic systems includes seminal contributions such as the
Rose-Nelson pump, the Higuchi-Leeper pumps, the Alzet and Osmet systems, the elementary
osmotic pump, and the push-pull or GITSR system. Recent advances include the development of Carewell Pharma
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the controlled porosity osmotic pump, systems based on asymmetric membranes, and other
approaches.
Delivery orifice
Polymer
Drug
Osmotic pump
Fig. 8: Osmotic pump
Osmotic agents:
Osmotic agents are used for the fabrication of the osmotie device maintain a
concentration gradient across the membrane by generating a driving force for the uptake of water
and assist in maintaining drug uniformity in the hydrated formulation. Osmotic agents usually
are ionic compounds consisting of either inorganic salts such as sodium chloride, potassium
chloride magnesium sulphate, sodium sulphate, potassium sulphate and sodium bicarbonate.
Additionally, sugars such as glucose, sorbitol, sucrose and inorganic salts of carbohydrates can
also act as effective osmotic agents.
References:
[1].Chien YW. Novel Drug Delivery Systems, 2nd Ed, New York: Marcel Dekker Inc.:
New York, 2007.
[21.Jain NK. Controlled and Novel Drug Delivery, 1st edition, published by CBS
Publishers and Distributors, New Delhi. 1997.
[3]. Stewart SA, Domínguez-Robles J, Donnelly RF, Larrañeta E. Implantable Polymeric
Drug Delivery Devices: Classification, Manufacture, Materials, and Clinical
Applications. Polymers (Basel). 2018;10(12):1379.
[41. Verma RK, Mishra B, Garg S. Osmotically controlled oral drug delivery. Drug Dev
Ind Pharm. 2000; 26 (7): 695-708. Carewell Pharma
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