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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5447_Библиотеки_им_академика_М_И_Перельмана
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Preparation of Aqueous Phase: 608g of water is charged in a stainless-steel vessel
and heated up to 70°C.
Preparation of Cream (O/W): The molten oil phase is transferred into aqueous
phase at 70 °C through a stainless-steel lter and simultaneously mixing it
slowly. The crude cream is passed through homogenizer for 10–15min while
temperature is maintained at around 70°C.
Incorporation of Drug in the Cream: Gentamicin is dissolved in in 86.17g of water
while mixing at 50°C.The drug solution is transferred into cream while stirring
at 50°C.
Homogenization: The nal cream product is passed and circulated through homog-
enizer for 10–15min. The temperature is lowered to 25°C during homogeniza-
tion. When the cream temperature reaches 25°C, it is ready for packaging.
10.3.2.3 Tests forEvaluation ofSemisolids
Evaluation of the quality attributes by various compendial and non-compendial tests
is required to assure good quality and avoid batch-to-batch variation.
Appearance
Providing qualitative description of the semisolid product is required to ascertain if
the product meets the acceptance criteria for appearance of nished dosage form
and packaging as specied and claimed by the manufacturer on the label. Any sort
of specic changes in the color and consistency such as discoloration, crystalliza-
tion, separation, shrinkage, grittiness, etc. should be identied by visual evalua-
tion [28].
Table 10.4 Formulation of gentamicin sulfate cream
Serial no. Material name Quantity (kg or g)
1. Gentamicin sulfate 1.82
2. White soft parafn 150
3. Cetomacrogol 1000 18
4. Cetostearyl alcohol 72
5. Chlorocresol 1.0
6. Liquid parafn 60
7. Monobasic sodium phosphate 3.0
8. Puried water 694.17
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Uniformity ofDosage Units
The extent of uniformity of the API amount among the dosage units of a semisolid
product should be determined to ascertain the consistency of dosage units. Both the
content uniformity and weight variation methods can be used for this test and are
discussed in the USP chapter, titled “Uniformity of Dosage Units” [29].
Water Content
Depending on the individual formulation, water content test ought to be performed
when considered appropriate and is discussed in USP chapter 921, titled “Water
Determination.”
Limits forPresence ofMicrobes
Unsterilized aqueous dermatological products should be assessed for presence and/
or amount of the microbes that have potential to cause skin infection and reduce the
pharmacological activity, such as Escherichia coli, Staphylococcus aureus,
Pseudomonas aeruginosa, and various Salmonella species. Additionally, the semi-
solid preparations intended for application at urethral, vaginal, and rectal sites
should be screened for presence of yeasts and molds [30].
Procedures for microbial tests should be performed according to methods dem-
onstrated in USP chapter 61 titled “Microbiological Examination of Nonsterile
Products: Microbial Enumeration Tests” and 62 titled “Microbiological Examination
of Nonsterile Products: Tests for Specied Microorganisms.” The acceptance crite-
ria for microbial count are given in USP chapter 1111.
Preservative Content
Standard concentration of the antimicrobial preservatives in semisolid products
should be demonstrated. Acceptance criteria is determined by the range of preserva-
tive content required for maintaining the microbial quality of drug during its shelf
life and usage.
Method and acceptance criteria for assessing the effectiveness of preservative are
demonstrated in the USP chapter 51.
Antioxidant Content
The tests for content of antioxidants should be determined if the drug product con-
tains antioxidants and the oxidative degradation cannot be detected by impurity test.
Standard concentration of antioxidants in semisolid products should be established.
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Acceptance criteria are determined by the range of antioxidant content required for
maintaining the stability of drug product during its shelf life and usage [31].
Sterility
Sterility of semisolid products that need to be sterile (according to pharmacopoeia)
such as ophthalmic ointments and products intended for application on burns or
open wounds should be ensured by sterility tests, such as the membrane ltration
method and direct inoculation test. Details of the test are given in the USP chapter 71.
pH
Semisolid products containing adequate amount of water or aqueous phase should
be tested for pH values before release of a batch for ensuring quality consistency
among various batches. The test is not included in pharmacopeial drug product
monograph; rather it is formulation dependent and specied by the manufacturer of
the drug product [19].
Particle Size
Semisolid drug products should be tested for particle size, shape, aggregation, or
crystal habit of the particles that have possibly occurred during the processing or
storage of these products. Such alterations may lead to the compromised quality of
the product. The test should be performed before release of a batch as well as at
specied stability time points for monitoring. The test is formulation dependent and
specied by the manufacturer of the drug product [32].
Apparent Viscosity
Rheological properties of the semisolid preparations should be tested by determina-
tion of the apparent viscosity. Details of the viscosity measurement procedure are
discussed in the USP chapter 911. The test is formulation dependent and specied
in individual monographs.
Uniformity inContainers
Uniformity of the semisolid drug product within packaging tubes and containers
should be evaluated as the product may have encountered phase separation or devia-
tion in physical appearance during manufacturing or storage. Thus, uniformity of
the dosage form should be evaluated before releasing a batch and during the shelf
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life for validation of product integrity. The procedure and acceptance criteria are
elaborated in the USP chapter 3.
10.3.3 Transdermal Patches
When drug is delivered through the skin to reach the systemic circulation, it is
termed as transdermal drug delivery (TDD). Transdermal drug delivery system is
used when systemic effect is desired. TDD is a safe, painless, and noninvasive
method of drug transport and it offers great advantage over other conventional deliv-
ery routes like oral, parenteral, and hypodermal shots. TDDS uses skin as drug
administration site. Drug is delivered by the aid of adhesive patches or other trans-
dermal devices like microneedles [33, 34].
A transdermal or skin patch is medicated adhesive patch which essentially deliv-
ers a specic dose of a medication to the circulation after passing through the skin
when placed on skin. Transdermal patches basically use a special membrane to
control the rate at which drug contained within the patch can pass through the skin
and into bloodstream in a controlled manner [35]. The patches were developed for
the rst time in the 1970s, and the rst patch approved by FDA was scopolamine
which was used for treatment of motion sickness. Transdermal patches applied on
the skin eliminate the need for vascular access by syringe or the use of pumps.
10.3.3.1 Basic Components ofTransdermal Patches
Polymer Matrix or Drug Reservoir
The polymer matrix or drug reservoir is the primary component used to control the
release of drug from patch. It should be nonreactive with active agent, biodegrad-
able, nontoxic, stable, and facilitate the uniform release of drug throughout.
The Drug
The drug to be incorporated in transdermal patch should be potent and non-irritating
and have short half-life, with low melting point and low molecular weight (˂400).
The drug in the patch should follow zero order kinetics of ow with broad therapeu-
tic index and low-dose requirements.
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Permeation Enhancers
Permeation enhancers are used to promote the sorption of drug from drug delivery
system onto the skin. Various solvents (methanol, ethanol, propylene glycol, isopro-
pyl palmitate), anionic surfactants (sodium lauryl sulfate, dioctyl sulfosuccinate),
nonionic surfactants (Pluronic F127 and F68), and bile salts are used as permeation
enhancers.
Pressure-Sensitive Adhesive
Pressure-sensitive adhesive is used for fastening the patch with the skin. The ideal
characteristics are that it should adhere with the skin without disturbing the normal
ora of the skin and retained on the skin while bathing or exercise. It should not
leave an unwashable residue and can be removed easily from the skin.
Backing Laminates
Backing laminates are impermeable and exible and prevent the drug to release
from the top of the patch. In transdermal patches, plastic backing with absorbent
pad, adhesive foam pad, and metallic plastic laminates are used.
Release Liner
Release liners are basically part of primary packaging material which avoids the
drug loss due to the escape of drug into the adhesive layer in the duration of storage.
It is composed of occlusive (polyethylene), nonocclusive (paper fabric), and a
release coating layer (Teon or silicon) [36, 37]
10.3.3.2 Types ofTransdermal Patches
Single-Layer Drug inAdhesive
In these patches, drug is contained in the adhesive layer. In these patches, adhesive
layer is responsible to adhere several layers together along with the skin as well as
to release the drug in a controlled manner [38].
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Fig. 10.4Figure 10.4 should be placed under 10.3.3.2section Graphical representation of the
different spatial distributions and layer thicknesses of the prototypes used to control multidrug
release [40]
Multilayer Drug inAdhesive
Basically, these are like single-layer system but separated by a membrane. In these
patches, one layer is designed for immediate release of drug while other layer is for
control release of drug from reservoir.
Reservoir Reservoir is considered as a separate layer of drug in liquid compart-
ment containing drug solution and suspension that are separated by the adhe-
sive layer.
Matrix The matrix system in these patches contains a layer of semisolid matrix in
which drug solution or suspension is present.
Vapor Patch In these patches, adhesive layer supports to combine various layers
together and release vapors as well. They basically provide essential oils and are
also used in conditions of decongestion and to aid in smoking cessation [39].
10.3.3.3 Advantages ofTransdermal Patches
– Topical patches are painless and noninvasive method to deliver substances
directly into body.
– Topical patches are best suitable for drugs that are broken down by stomach
acids and have extensive rst-pass effect.
– Topical patches deliver the drug in steady and controlled manner over longer
period of time.
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– Topical patches have lesser side effects as compared to oral medications.
– Topical patches are user-friendly.
– Topical patches are economical [41].
10.3.3.4 Manufacturing ofTransdermal Patches
Transdermal patches are manufactured by various methods. We will discuss few of
them here.
Circular Teon Mold Method
In this method organic solvents are used to dissolve various proportions of polymer
and drug. Plasticizers are added in the same drug polymer solution. Similarly, per-
meation enhancers are also added in the remaining half portion of the organic sol-
vent and then incorporated in the drug polymer solution. Afterward, the overall
solution is stirred for ~12h following addition into a circular Teon mold which has
been enclosed with an inverted funnel to regulate solvent vaporization placed in a
laminar ow hood (LFH) on a levelled surface for 24h. The dried lms obtained
were kept for 24h at 25±0.5°C in a desiccator before evaluation [5] .
Asymmetric TPX Membrane Method
A transdermal patch can be prepared with heat-sealed polyester lm supported by a
backing membrane having concave diameter of approximately 1.0cm. The drug is
dispensed into the concave membrane covered with TPX asymmetric membrane
and sealed by an adhesive. TPX {poly(4-methyl-1-pentene)} asymmetric mem-
brane can be fabricated by utilizing dry/wet inversion process. A polymer solution
is prepared by dissolving TPX in a mixture containing solvent (such as cyclohex-
ane) and non-solvent additives at 60°C temperature. The polymer solution is then
kept for 24h at 40°C followed by casting on a glass plate with a predetermined
thickness control by using a Gardner knife. A lm is formed by evaporating the
organic solvent at 50°C for 30s and immediately immersed in a coagulation bath
already maintained at 25 °C temperature. Ten minutes after the immersion, the
membrane is removed and air-dried in a circulation oven for 12h at 50°C. The
release of drug from the TPX asymmetric membrane is dependent on the structure
of membrane which can be fabricated by varying the non-solvents in casting solu-
tion [42].
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EVAC Membrane Method
Ethylene vinyl acetate copolymer (EVAC) membranes are utilized as control-release
transdermal patches. One percent of Carbopol reservoir gel, polyethylene (PE), or
in case of water-insoluble drug propylene glycol is the choice of EVAC.Drug dis-
solution in PE or PG is carried out, and Carbopol gel resin will be incorporated and
neutralized with 5% solution of sodium hydroxide. The drug in the gel is employed
over the backing layer and rate controlling membrane will be placed over the drug
containing gel and hermetically sealed by heat to avoid leakage [43].
Some other methods like aluminum-backed adhesive, IPM membrane, mercury
substrate, proliposome, and free lm can be used for the manufacturing of transder-
mal patches.
10.3.3.5 Quality Control Parameters
Physical Appearance
Physical appearance of patches is checked visually for color, clarity, and surface
texture.
Weight Variation
Weight variation is checked by cutting 2×2cm
2
from the lm and weight on elec-
tronic balance.
Thickness
Thickness of patch is measured at three different places with the help of vernier cali-
per and average thickness is calculated.
Tensile Strength and% Elongation
The tensile strength at breaking point of lm is measured with the help of a pulley
base tensile strength apparatus:
Tensilestrength
tensileload at break
Crosssectionalarea
=
(10.1)
The % elongation is calculated by noting the length just before the breakpoint by the
following equation [44]:
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%Elongation
Finallengthinitiallength
initiallength
x
100
(10.2)
Folding Endurance
Folding endurance can be measured by repeatedly folding a 2cm
2
strip at a same
point until it breaks. The value of folding endurance is determined by the number of
times the lm is folded at same point without being broken.
Percent Moisture Loss
Percent moisture loss is calculated by weighing individual patch and keeping them
in a calcium chloride containing dessicator. The nal weight is noted when no fur-
ther change is observed in weight. The % moisture loss is calculated with the help
of the following equation [45]:
Moisturecontent
Initialweight Finalweight
Initialweight
x%
1000
(10.3)
Percent Moisture Uptake
Percent moisture uptake is calculated by weighing the individual patch and placing
them in a desiccator and humidity is maintained 80–90% RH with the help of satu-
rated solution of ammonium chloride. The patches are kept until no more change is
observed in weight. Percent moisture uptake is calculated with the help of the fol-
lowing equation [46]:
Moistureuptake
Initialweight Finalweight
Initialweight
x%
100
(10.4)
Drug Content Uniformity
Drug content is calculated by cutting the patch 2cm
2
and dissolved in phosphate
buffer solution on a magnetic stirrer for 24h, and drug content is determined on
UV-visible spectrophotometer or HPLC.
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10.3.3.6 Therapeutic Applications ofTransdermal Patches
Mostly sold patches in the USA is nicotine patch, which releases nicotine in a con-
trolled manner to assist in cessation of tobacco. Two opioid medications that pro-
vide relief from severe pain are fentanyl (Duragesic) and buprenorphine (BuTrans).
Estrogen patches are used to control menopausal symptoms. Nitroglycerin patches
are used for angina.
10.3.4 Transdermal Microneedles
Basically, microneedles are of micron-sized needles which can penetrate easily
through epidermal and dermal layer without pain.
Microneedles’ height ranges from 10 to 200 micrometer and a width of
10–50micrometers. Microneedles are widely used in TDDS because they are safe,
efcient, painless, and convenient. Microneedles are the rationalized way to deliver
the drug through the skin. Through microneedles large molecules can be adminis-
tered. In contrast to the hypodermic needles, microneedles facilitate faster healing
of injection sites and lower microbial penetration. First-pass metabolism is also
avoided [47, 48].
10.3.4.1 Types ofMicroneedles
Microneedles are made up of insoluble metal alloys (such as titanium, stainless
steel, nickel iron), insoluble silicon, and biodegradable polymers such as polyvinyl-
pyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA), carboxymethyl cellulose
(CMC), hyaluronic acid, etc.
Based on the design and drug delivery principle, microneedles are divided into
four classes.
Solid Microneedles
Solid microneedles basically create microchannel in stratum corneum. It generally
increases the permeability by creating microchannels in the skin, and the drug is
rubbed over that area or the needles are coated with drug. The microneedles use
passive diffusion pathway [49].
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