The document discusses topical and rectal drug delivery. It describes the structure of the skin and factors affecting percutaneous absorption of drugs through the skin. Some key topical formulations include ointments, creams, gels, and pastes. Rectal drug delivery can be used for local treatment of conditions or systemic drug delivery when oral administration is not possible. Rectal dosage forms include suppositories, creams, ointments, and solutions/suspensions. Absorption of drugs from the rectum depends on physiological and physicochemical drug factors.

1. Topical and Rectal
absorption of drugs,
formulation and
evaluation
Department of Pharmaceutical science
Dr. Harisingh Gour Vishwavidyalaya, Sagar
M.P.
Prepared by:
Name - Amit Sahu
Roll No. – Y21254005
M. Pharma 1st Sem.
Submitted to:
Prof. Sanjay K. Jain
Dr. Dharmendra Jain

2.  Topical drug delivery
The application of a formulation to the skin to treat a local
disorder, i.e. the active pharmaceutical ingredient acts within the
skin or at the underlying tissue.
 Introductions

3.  Structure of the skin
1. Epidermis
 The epidermis is approximately 50 - 150μm thick and consists
largely of constantly renewing, outward moving cells called
keratinocytes.

4.  The outermost layer of the epidermis is the stratum corneum or
horny layer, which consists of compacted, dead, keratinized cells
in stratified layers with a density of 1.55.
 The stratum corneum is the rate-limiting barrier that restricts
the inward and outward movement of chemical substances.
2. Dermis
 A layer typically 3 mm to 5 mm thick that is the major
component of human skin.
 The dermis is composed of a network of mainly collagen and
elastin in a mucopolysaccharide gel; essentially this combination
provides an aqueous environment.

5.  Contained and supported within the dermis are numerous blood
vessels, lymphatics, and nerves, as well as the epidermal
appendages such as the hair follicles, sebaceous glands, and sweat
glands.
3. Hypodermis
 The dermis rests on the hypodermis (subcutis) which is composed
of loose fatty connective tissue.
 Its thickness varies considerably over the surface of the body as
well as between individuals.

6.  Percutaneous Absorption
Drug dissolution in vehicles
Drug diffusion through vehicle to skin
Trans follicular
route
Trans epidermal
route
Partitioning into
sebaceous gland
Partitioning into
stratum corneum
Partitioning into
viable epidermis
Diffusion through viable epidermis
Diffusion through upper dermis
Systemic circulation

8.  Factors affecting Percutaneous
absorption of drugs:
 Solubility and partition co- efficient
 pH condition
 Penetrant concentration
1. Physicochemical properties of permeant molecule
2. Physiological and pathological condition of skin
 Lipid film
 Skin hydration
 Skin temperature

9. 3. Biological factors
 Effect of vehicle
 Pathological injury to skin
 Skin age
 Thickness of Stratum Corneum
 Skin condition
 Chronic use of certain drugs
 Presence of hair follicles
 Blood flow
 Regional skin sites
 Species difference

10.  Topical formulations
1. Liquid preparations
I. Ointments
II. Gels (jellies)
III. Creams
IV. Pastes
2. Semisolid Preparations
3. Aerosols
I. Lotion
II. Liniment
III. Collidines
2. Solid Preparations I. Powders

11.  Formulation consideration
1. Drug Selection
 The ideal properties of a molecule penetrating stratum
corneum:
 Low molecular mass, preferably less than 600 Da.
 Adequate solubility in oil and water.
 High but balanced (optimal) partition coefficient.
 Low melting point.
 Insoluble drugs must be uniformly dispersed throughout the
vehicle to ensure homogeneity of the product.

12. 2. Vehicles/Semisolid Bases:
The USP recognizes four classes of semisolid bases under the
general classification of ointment
I. Oleaginous Bases
Hydrocarbons Petrolatum (soft paraffin)
Mineral oil (liquid paraffin)
Hydrocarbon waxes (hard paraffin)
Vegetable oils Peanut Oil, Almond Oil, Sesame Oil, Olive
Oil
Oily silicones Dimethicone and Cyclomethicone

13. II. Absorption Bases
These bases are usually anhydrous and they do absorb aqueous
solutions, these are two types
Anhydrous absorption bases:
Hydrous absorption bases:
 These are w/o emulsions with ability to absorb additional water.
 Eg. Hydrous lanolin
 They absorb water to form water-in-oil emulsions.
 Eg. Anhydrous lanolin (wool fat), beeswax, hydrophilic
petrolatum and organosilicones

14. III. Water-removable Bases:
 The water-removable bases are oil-in-water emulsions and are
referred to as “creams.”
 The vanishing cream bases fall into this category.
 The vanishing creams are so termed because upon application
and rubbing into the skin, there is little or no visible evidence of
their former presence.
IV. Water-soluble Bases:
 Water-soluble vehicles are prepared from mixtures of high-
and low molecular-weight polyethylene glycols or macrogol,
which have the general formula: HOCH2 [CH2OCH2 ]n
CH2OH.

15. 3. Penetration Enhancers:
 Materials which increase the rate of absorption of topically
applied drugs.
 These agents are often called “accelerants” or “sorption
promoters” or “penetration enhancers”.
Penetration
enhancers
Examples Mechanism of action
Sulphoxides Dimethyl sulfoxide
Dimethylacetamide
Dimethylformamide
Skin damage, Denature
proteins, Convert keratin
conformation from -
helical to -sheet, lipid
fluidization
Decylmethylsulfoxide

16. Pyrrolidones N-methyl-2-pyrroli
done 2 pyrrolidone
Alter solvent nature of
membrane, generate
reservoir within skin
Fatty acids Oleic acid, Lauric
acid, Linoleic acid,
Linolenic
Interact and modify SC
lipid bilayers, Lipid
fluidization
Alcohols,
glycols
Ethanol, Octanol,
Propylene glycol,
Transcutol
Increase drug solubility and
thermodynamic activity,
extract lipids from SC,
Surfactants Sodium lauryl
sulphate, Cetrimide
Increase transepidermal
water loss, changes
membrane permeability

17. 4. Emulsifiers :
 The water-soluble soaps were among the first emulsifiers used for
semisolid oil-in-water emulsions.
 The viscosity of the cream or ointment prevents coalescence of
the emulsified phases and helps to stabilize the emulsion.
 The addition of fatty polar substances, such as cetyl alcohol and
glyceryl monostearate, tends to stabilize the semisolid oil-in-
water emulsion.
5. Humectants :
 Glycerine, propylene glycol, sorbitol 70%, and the lower
molecular weight polyethylene glycols are used as humectants
in creams.

18. 6. Preservatives:
 The preservatives are added to semisolids to prevent
contamination, deterioration, and spoilage by bacteria and
fungi, since many of the components in these preparations serve
as substrates for these microorganisms.
 Methylparabens and propylparabens, Quaternary ammonium
compounds (e.g. benzalkonium chloride) or the phenylmercuric
salts.
 Boric acid may be used in the ophthalmic preparations.

19. 7. Antioxidants:
 Antioxidants are added to semisolids whenever oxidative
deterioration is anticipated.
 Commercial used antioxidants are Butylated hydroxy anisole
(BHA), Butylated hydroxy toluene (BHT), Propyl gallate.

20.  Evaluations:
1. Extrudability and spreadability:
 Ease with which semisolid come out from tube or pack and ease
with which it spreads over skin is designated as extrudability and
spreadability, respectively.
 Force required, making the ointment move out or extrude through
uncapped tube, placed below the plunger is test of extrudability.

21.  In spreadability test, a small quantity of ointment is placed
between two slides one of which is movable.
 Force is applied to movable slide and the corresponding
distance traveled is recorded.
 Graphical plots between
applied force and
distance traveled indicate
spreadability.

22. 2. In vitro diffusion study:
 Franz diffusion cell was used for the drug release studies.
 Ointment was evenly applied onto the surface of cellulose
membrane.
 The cellulose membrane was
clamped between the donor
and the receptor chamber of
diffusion cell.
A. Diffusion method

23.  The receptor compartment was filled with phosphate buffer pH 7.4,
and the assembly was maintained at 37°C ± 0.5 under constant
magnetic stirring.
 300 mg of ointment was applied to the membrane on the donor
compartment and then covered with aluminum foil to prevent
drying out.
 Aliquots were withdrawn at predetermined time intervals over a
period of 1h and amount of drug released was analyzed by using
UV spectrophotometer.
B. Agar cup plate method:
 This method is generally based on diffusion pattern of base and
which drug transfer spontaneously from region of higher
concentration to lower concentration.

24.  Make a hole at the center of agar plate with the help of hollow
glass rod and fill the ointment formulations.
 Plates are keep aside to determine the releasing property by
measuring the radius (or) diameter of colored zone at ½,1,1½, 2,
2½, and 3 hours time intervals.

25. 3. Ex vivo permeation study:
 The prepared rat skin was mounted on the Franz diffusion cell
(with effective diffusion area 3.14 cm2 and 7 ml cell volume)
with stratum corneum facing upward.
 The receptor compartment was filled with phosphate buffer pH
7.4, and the assembly was maintained at 37°C±0.5 under constant
magnetic stirring.
 The amount of drug permeated through rat skin was carried out as
per method described in diffusion study.

26. 4. Irritation test:
 Allergy or irritation due to a specific ointment base component is
more frequent and more important, hence a number of test
procedures have been devised to test irritancy level of an ointment
formulation.
 Irritation potential of formulation is evaluated
 In vitro—HET CAM test on eggs,
 In vivo—Draize dermal irritation test on rabbits and
 In humans—Draize-Shelanski Repeat Insult Patch Test.

27.  Rectal drug delivery
 The rectal route may represent a practical alternative and can be
used to administer drugs for both local and systemic actions.
 This includes the local treatment of constipation, hemorrhoids,
anal fissures, inflammation, and hyperkalemia.
 Rectal formulations for systemic
drug delivery are used clinically
for the treatment of pain, fever,
nausea and vomiting, migraines,
allergies, and sedation.

28.  The reasons for choosing the rectal route for
systemic drug administration:
 The patient is unable to swallow. This is the case with
unconscious patients, preoperatively and postoperatively,
patients with gastrointestinal tract problems, very young or
very old patients, and patients with certain central nervous
system (CNS) disorders, such as epilepsy.
 The drug under consideration is not well suited for oral
administration; for example, drugs causing gastrointestinal side
effects, unpalatable drugs and those which are susceptible to
extensive first-pass metabolism and enzymatic degradation in
the gastrointestinal tract.

29.  ABSORPTION OF DRUGS FROM
THE RECTUM:
Insertion of the dosage form into the rectum
Suspended drugs leave the vehicle
Dissolve in the rectal fluid
Dissolved drug molecules will diffuse through the rectal mucus
Then into the epithelium of the rectal wall
membrane by the passive diffusion process.

30.  FACTORS AFFECTING THE ABSORPTION
OF DRUG FROM RECTUM:
1) Physiological factors of drug:
 Colonic content - Drug will have greater opportunity to get
absorbed when the rectum is empty. For this purpose enema is
given before rectal drug administration.
 Circulation route – If the drug is absorbed from lower
hamorrhoidal veins it will directly take the drug to inferior
venacava, so the absorption will be rapid and effective.
 pH and lack of buffering capacity of rectal fluids - The
rectal fluid have pH 7-8, hence no effective buffering capacity.
So ionized or un-ionized form of the drugs will be having
marked influence.

31. 2) Physicochemical factors of drug:
 Lipid-water solubility – A lipophilic drug if given with
fatty bases it will not escape from base easily. So absorption
is altered.
 Particle size – The smaller the particle the greater will be the
solubility.
 Nature of base- If the base interacts with the drug or if it
irritates the mucus membrane it will decrease the absorption.
Mainly in case of suppositories.

32.  Rectal semisolids: 1) Creams
2) Gels
3) Ointments
4) Suppositories
 Rectal liquids: 1) Solutions
2) Suspensions
 Rectal aerosols
 DIFFERENT TYPES OF RECTAL
DOSAGE FORMS:

33.  RECTAL SEMISOLIDS:
 Rectal cream, gels and ointments
 These preparations are used for topical application to the perianal
area for insertion within the anal canal. They largely are used to
treat inflammation, the pain and discomfort.
 The drugs includes astringents (eg. Zinc oxide), protectants and
lubricants (eg. Cocoa butter, lanolin), local anaestheics (eg.
Lidocaine HCL), and anti inflammatory agents (eg.
Hydrocortisone)
 The bases used in anorectal creams and ointments includes
combinations of polyethylene glycol 300 & 3350, emulsion cream
bases using cetyl alcohol & cetyl esters wax, and white petroleum
and mineral oil.

34.  The preservatives like methylparaben, propylparaben,
benzylalcohol and Antioxidant butylated hydroxyanisole (BHA)
are also used.
 Several commercial rectal creams and ointments and
gels:
1. RECTOGESIC ointment - Glyceryl trinitrate
2. ANOBLISS Cream - Lidocaine + Nifedipine
3. ANALPRAM - HC cream - Pramoxine + Hydrocortisone
4. DIASTAT Gel - Diazepam

36.  APPLICATION - Before applying rectal ointments and
cream the perianal skin and the affected area should be
cleaned and dried.
 Special types of applicators are used for applications of
creams & several market preparations are available with
perforated applicator tips and inserters.
Fig. Rectal cream and ointment
applicator
Fig. Rectal gel inserter

37.  SUPPOSITORIES:
 These are generally intended for use in the rectum, vagina, and to
a lesser extent, the urethra for local or systemic effects.
 Rectal suppositories
 Typically, these are torpedo-shaped dosage forms, usually
employ vehicles that melt or soften at body temperature.
 Vary in weight from 1 g (children) to 2.5 g (adult).
 Suppositories are ovoid or conical medicated
solids intended for insertion into one of the
several orifices of the body, excluding the
mouth.
 This term derives from the Latin suppositus,
meaning “to place under.”

38.  SUPPOSITORY BASES:
 The Ideal Suppository Base :-
1) The majority of components melt at rectal temperature 36°C.
2) The base is completely nontoxic and nonirritating.
3) It is compatible with a broad variety of drugs.
4) It has no metastable forms.
5) It shrinks sufficiently on cooling to release itself from the
mold without the need for mold lubricants.
6) It is nonsensitizing.
7) It has wetting and emulsifying properties.

39. 8) It is stable on storage, i.e. does not change color, odor, or drug
release pattern.
9) It can be manufactured by molding by either hand, machine,
compression, or extrusion.
Oleaginous base Aqueous base Emulsifying base
Suppository Base

40. A. Oleaginous base:
 Cocoa butter is the most widely used suppository base.
 It satisfies many of the requirements for an ideal base.
 Cocoa butter is primarily a triglyceride, yellowish-white, solid,
brittle fat, which smells and tastes like chocolate.
 Its melting point lies between 30°C and 35°C.
B. Oleaginous base
i. Glycerogelatin: It is a mixture of glycerin, water and gelatin.
ii. Soap glycerin: In this case, soap is employed instead of glycerin
for hardening.
iii. PEG bases: Postonals, Carbowaxes and Macrogols.

41. C. Emulsifying base
 These are synthetic bases and a number of proprietary synthetic
bases are available in the market.
 Eg. Witepsol, Massa estarinum, Massuppol

42.  MANUFACTURE OF SUPPOSITORIES:
A. Hand Molding:
 The simplest and oldest method of preparing a suppository is by
hand.
 The base is first grated and then kneaded with the active
ingredients by use of a mortar and pestle, until the resultant mass is
plastic and thoroughly blended.
 The mass is then rolled into a cylindric rod of desired length and
diameter, of the intended weight.
 Starch or talcum powder on the rolling surface and hands prevent
the mass from adhering.

44. B. Compression Molding:
 The cold compression method is simple and results in a more
elegant appearance than does hand molding.
 It avoids the possibilities of sedimentation of the insoluble solids
in the suppository base, but is too slow for large-scale production.

45. C. Pour Molding:
 The most commonly used method for producing suppositories on
both a small and a large scale is the molding process.
 First, the base material is melted and then the active ingredients
are either emulsified or suspended in it.
 Finally, the mass is poured into cooled metal molds, which are
usually chrome-or nickel-plated.

46.  Lubrication of mould :
Sr. No. Base Lubricants
1. Cocoa butter Soft soap, Glycerin, Alcohol 90%
2. Glycero-gelatin Liquid paraffin or Arachis oil
3. Emulsifying base No lubricant is used.
 Dosage Replacement Factor / Displacement value:
 The amount of base that is replaced by active ingredients in the
suppository formulation can be calculated.
 The replacement factor, f, is derived from the following equation:
𝒇 =
𝟏𝟎𝟎 𝑬 − 𝑮
𝑮 (𝑿)
+ 𝟏
 Where, E is weight of pure base
suppositories, G is weight of
suppositories with X% active
ingredient.

47.  EVALUATION OF SUPPOSITORIES
 Weight Variation
 Weight variation test is run by weighing suppositories individually
calculating the average weights and comparing the individual
tablet weights to the average.
 The value of weight variation test is expressed in percentage.
 The following formula is used:
𝑾. 𝑽. =
𝑰𝒏𝒅𝒊𝒗𝒊𝒅𝒖𝒂𝒍 𝒘𝒕. − 𝑨𝒗𝒆𝒓𝒂𝒈𝒆 𝒘𝒕.
𝑨𝒗𝒆𝒓𝒂𝒈𝒆 𝒘𝒕.
× 𝟏𝟎𝟎
 No suppositories should deviate from average weight by more
than 5%.

48.  Hardness (fracture point)
 Hardness test or fracture point test is determine the tensile
strength of the suppositories to access whether they will be able to
withstand the hazards of packing and transporting.
 Hardness test of the suppositories done by using Monsanto
hardness tester.
 The weight required for suppository to collapse will considerd as
hardness of the suppository.

49.  Macro Melting Range Test
 Measure of the time it takes for the entire suppository to melt
when immersed in a constant temperature (37°C) water bath.
 In contrast, the micromelting range test is the melting range
measured in capillary tubes for the fat base only.
 The suppository melting point apparatus by ERWEKA® consists
of a graduated tube like glass test chamber.
 The sample to be tested is placed in a spiral
shaped glass test basket inside the test
chamber which itself is surrounded by a
water jacket heated by circulation thermostat.
 The time for the entire suppository to melt or
disperse in the surrounding water is
measured.

50.  Softening Time Tests
 Softening time test apparatus consists of
a U-tube partially submersed in a
constant-temperature water bath.
 A constriction on one side holds the
suppository in place in the tube.
 A glass rod is placed on top of the
suppository, and the time for the rod to
pass through to the constriction is
recorded as the “softening time”.
 BreakingTests
 The breaking test is designed as a method for measuring the
fragility or brittleness of suppositories.

51.  The apparatus used for the test consists of a double-wall
chamber in which the test suppository is placed.
 Water at 37°C is pumped through the double walls of the
chamber, and the suppository, contained in the dry inner
chamber, supports a disc to which a rod is attached.
 The other end of the rod consists of another disc to which
weights are applied.
 The test is conducted by placing 600 g
on the platform.
 At 1 min intervals, 200 g weights are
added, and the weight at which the
suppository collapses is the breaking
point

52.  References:
1. Aulton M. E., Taylor K. M., “Aulton’s Pharmaceutics The Design
and Manufacture of Medicines”, 5th edition, Elsevier
publications New York, 2018, page no. 715-737, 740-749.
2. Gennaro A. R., Remington: “The Science and Practice of
Pharmacy”, 20th edition, volume – I, Lippincott Williams &
Wilkins publications, Philadelphia,2001, page no. 836-850, 855.
3. Lachman L., Liberman H. A., Kanig, J. L., “The Theory and
Practice of Industrial Pharmacy”, 3rd edition, Varghesh
publishing house Bombay, 1991, page no. 534-562.
4. MARU A.D., LAHOTI S.R., "Formulation and Evaluation of
Ointment Containing Sunflower Wax", Asian Journal of
Pharmaceutical and Clinical Reserch, 2019.

53. 5. Rao V., Reshma D., Padmalatha, "Invitro Evaluation of Salicylic
Acid Release from an Ointment and Cream By Agar Plate
Method", World Journal Of Pharmacy And Pharmaceutical
Sciences, 2014.
6. Zuikina Y., Polovko N., Strilets O., Strelnikov L.,"The in vitro
Release Testing and The Antimicrobial Activity of Semi-solid
Dosage forms which contain Salicylic acid", Farmacia, 2021.
7. Gupta A. , Mishra A. K., Singh A. K. , Gupta V., Bansal P.,
“Formulation and evaluation of topical gel of diclofenac sodium
using different polymers”, Drug Invention Today Vol.2.Issue
5.May 2010
8. Baviskar P, Jaiswal S, Sadique S, Landged A. Formulation and
evaluation of lornoxicam suppositories. The Pharma Innovation.
2013 Sep 1;2(7, Part A):20.