Semisolid Course 2

7/28/2019 Semisolid Course 2

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Semisolid Dosage Forms (4 CU).(Transdermal drug delivery system)

- Definitions and types of semi-solid

-Anatomy of the skin.

- Mechanisms of drug penetration through skin.

- Semisolid bases and their selection.

-General formulation of semisolids (ointment and gel),

manufacturing procedure, evaluation and packaging.-Transdermal therapeutic systems (TTS); types andpreparation.

-Novel mechanisms and devices to enhance skin delivery; Penetrationenhancers, types and mechanism of action; Liposomes and other vesicles;Electrically assisted transdermal delivery system (iontophoresis andelectroporation). Sonophoresis, high velocity particles and stratumcorneum abletion.


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Solid dosage formsa. Tablets (8 cu)

-Introduction to unit solid dosage forms; tablets

Tablet exciepients

Formulation of tablets; tablet machines (single

punch and rotary press machine).

Granulation techniques; wet and dry

granulation.-Tablets prepared by direct compression.

a. Tablets (cont.)

Tablet coating; Type of tablet coating (sugar, filmand compression coat), methods of coating,functional coat.

Tablet standers.

Problems associated with tablet manufacture(e.g Lamination, Capping, sticking, picking,)

Quality control tests for tablets (weight variation,disintegration, dissolution, thickness anddiameter, friability).


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B. Molded solid dosage forms ;suppositories(4 cu) .

Anatomy of the rectum and vagina.

Factors affecting drug release from suppositories;physiological and physicochemical considerations.

Ideal requirements, bases, manufacturingprocedure, packaging and evaluation.

Formulation

Quality control testsPackaging and storage

C. Capsules (2CU).- Advantage and disadvantages of capsule dosage form,material for production of hard gelatin capsules, size ofcapsules.

- Methods of capsule production, soft gelatin capsule shelland capsule content, importance of base absorption andminim/gm factors in soft capsules.

- Quality control, stability testing and storage of capsule

dosage forms.Microcapsulation (2CU).-Types of microcapsules; importance of microencapsulation in pharmacy.

-Microcapsulation by phase seperation, co-acervationmultiorifice, spray drying, spray congealing, polymerization,complex emulsion, air suspension technique, coating panand other techniques.


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D. Micromeritics (2CU).Particle size and size distribution.

Methods for determining particle size.

Particle shape and surface area.

Porosity.

Densities of particles.

Methods used for determination of powderdensity, with practical examples

Flow properties.Compaction.

Semisolid Dosage Forms


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IDEAL PROPERTIES OF SEMISOLID

DOSAGE FORMS

1- PHYSICAL PROPERTIES:

a)Smooth texture

b) Elegant in appearance

c) Non dehydrating

d) Non gritty

e) Non greasy and non staining

f) Non hygroscopic

IDEAL PROPERTIES OF SEMISOLIDDOSAGE FORMS

2-PHYSIOLOGICAL PROPERTIES:

a) Non irritating

b) Do not alter membrane / skin functioning

c) Miscible with skin secretion

d) Have low sensitization effect3-APPLICATION PROPERTIES:

a) Easily applicable with efficient drug release

b) High aqueous washability


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TYPES OF CONVENTIONAL SEMISOLID

DOSAGE FORMS

1-OINTMENTS:

They are soft hydrocarbon based semisolid

preparations, composed of fluid hydrocarbon

meshed in a matrix of higher melting solid

hydrocarbon, e.g. pertrolatum.

Since they are of greasy nature so they stain

cloths, are generally poor solvent for most drugs,

and usually decrease the drug deliverycapabilities of the system.

TYPES OF CONVENTIONAL SEMISOLIDDOSAGE FORMS

2-CREAMS:

They are viscous semisolid emulsion systemwith opaque appearance compared with thetranslucent ointments. Consistency andrheological characters depend on weather the

cream is w/o or o/w.Properly designed O/W creams are elegant drugdelivery system, pleasing in both appearanceand feel after application.

O/W creams are non greasy and are rinsable.

They are good for most topical purposes.


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TYPES OF CONVENTIONAL SEMISOLID

DOSAGE FORMS

3-PASTES:Pastes are basically ointments into which a highpercentage of insoluble solid has been added. Theextraordinary amount of particulate matter stiffens thesystem.

Pastes are less penetrating than ointment .

Paste make particularly good protective barrier whenplaced on the skin for, in addition to forming an unbrokenfilm, the solid they contain can absorb and thereby

neutralize certain noxious chemicals before they everreach the skin .

Like ointments, paste forms an unbroken relatively waterimpermeable film. Unlike ointments, the film is opaqueand therefore, an effective sun block accordingly.

TYPES OF CONVENTIONAL SEMISOLIDDOSAGE FORMS

4-GELS (JELLIES):Gels are semisolid coherent system inwhich a liquid phase is constrainedwithin a polymeric matrix (consisting ofnatural or synthetic gum) having a highdegree of physical or chemical cross-linking .

Gels are transparent or translucent

non-greasy semisolid gels .Some are as transparent as wateritself, an aesthetically pleasing state,other are turbid, as the polymer ispresent in colloidal aggregates thatdisperse light .

They are used for medication orlubrication.


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Conventional topical vehicles, such as

ointments, creams or gels, predominantly exerttheir effect by releasing the drug onto the skinsurface, and the drug molecules then diffusethrough the skin layers. The extent and durationof diffusion depends on the (1) physicochemicalproperties of the drug, (2) the type of base and(3) skin condition.

In general, the modification of drug absorptionkinetics by these vehicles is the result of their

ability to provide increased hydration byocclusion or some other mechanism.

Functions

Structure


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Structure of the skin: its barrierproperties

The skin is the largest organ of the body and acts as aprotective barrier with sensory and immunologicalfunctions.

Human skin is, on average, 0.5 mm thick (ranging from0.05 mm in eye lid to 2 mm).

Classification of skin based on the epidermis aloneespecially the surface layer (stratum corneum):

- thick: palms of hand, soles of feet

- thin: rest of the body

Although the skin is one of the major sites for non-invasive delivery of therapeutic agents into the body, thistask can be relatively challenging owing to theimpermeability of the skin.


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Skin Structure

The skin consists of three major layers:

- Epidermis

- Dermis

- Subcutaneous tissues

Skin Structure

Schematic cross section of the skin


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Skin Structure

Skin Structure

1. Epidermal layer:

- Stratum Corneum (SC) or horny layer

- Viable epidermis


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Viable epidermis

The viable epidermis consists of multiple layers ofkeratinocytes at various stages of differentiation.

Does not contain blood vessel but contain nerve endingfor touch and pain.

The role of the viable epidermis in skin barrier function ismainly related to the intercellular lipid channels.

Depending on their solubility, drugs can partition fromlayer to layer after diffusing through the SC.

contains metabolic enzymes

Cell types:

Keratinocytes: produce keratine

Melanocytes: produce melanine

Langrhans cells: immune cells, defense mechanism

Layers of epidermis


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Preparations for dermal use

Preparations for transdermal use

(percutaneous absorption)


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The skin

The most extensive and readily accessible organCovers a surface area of approximately 2 m2

Receives about one-third of the blood circulation.

Composed of three tissue layers:

Epidermis

Dermis

Subcutaneous fat tissue or hypodermis

Skin structure


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Possible Routes of Skin Penetration

Drugs can penetrate skin barrier by three routes:

-Transcellular (across cells)

-Intercellular (between cells)

-Transappendageal (via hair follicles, sweatand sebum glands)

Percutaneous drug absorption results from direct

penetration through the stratum corneum, followedby passing through the epidermal tissues and intothe dermis.

Pathways of drug penetrationthrough skin

Simplified diagrams showing routes of drug penetration.

(a) Macroroutes of drug penetration (1) across the continuous stratum

corneum; (2) through the hair follicles with their associated sebaceous

glands or (3) via the sweat duct.

(b) Representation of the stratum corneum membrane, illustrating two

possible microroutes for permeation. (1) Intercellular (2) transcellular


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Micro-routes of Penetration through SC

Penetration through SCcould be:- Trans-cellular pathway

- Inter-cellular pathway

Schematic of Skin Absorption


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Process of transdermal permeation.

RATIONAL APPROACH TO TOPICALFORMULATION

In dermatology, we aim at five main target regions: skin

surface, horny layer, viable epidermis and upper dermis,

skin glands, and systemic circulation

(1) Surface treatment

We care for the skin surface mainly by using cosmetic

application, by forming a protective layer, or by attacking

bacteria and fungi.( sunscreens, barriers that hinder

moisture loss, antimicrobials and insect repellants)

(2) Stratum corneum treatment

The main therapies aimed at the horny layer improve

emolliency by raising water content or stimulating

sloughing (keratosis, Exfolients such as salicylic acid).


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RATIONAL APPROACH TO TOPICAL

FORMULATION

(3)Skin appendage treatment

Antiperspirants (aluminium) reduce hyperhydrosis of thesweat glands. Depilatory,Topical antibiotics, Antifungals,Exfolients for acne treatment.

(4) Viable epidermis and dermis treatment

We can treat many diseases provided that thepreparation efficiently delivers drug to the receptor (anti-inflammatory, anesthetic, antihistamine).

RATIONAL APPROACH TO TOPICALFORMULATION

(5) Systemic treatment via percutaneous absorption

In recent years considerable scientific work has led the

route being used to treat several conditions by means of

transdermal patches (e.g. motion sickness (hyoscine),

angina (nitroglycerin).


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The fraction of the drug that penetrate the

skin via any route depends on:

The physicochemical nature of the drug,

specially its size, solubility and partition

coefficient

The site and condition of the skin

The formulation How vehicle component temporarily change

the properties of the stratum corneum


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Ideal molecular properties for drug

penetration

A low molecular weight (generally less than 500

Daltons)

An adequate solubility in oil and water

A balanced partition coefficient

A low melting point

Potent drug (maximum 50 mg/day)

Factors Affecting Transdermal

Delivery

Physiological factors

Physicochemical factors


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PHYSIOLOGICAL FACTORS

1. Skin condition Intact skin is a barrier

Damaged skin more permeable

Diseased skin usually more permeable

2. Skin age

- babies and children greater area/weight thanadult- absorb more drug e.g. steriod

- premature infants- no stratum corneum- e.g. the use of topical caffeine for breathingdifficulties

3. Regional skin site

- wide variation e.g face to foot

Effect of Nitrogl ycerin on Systol ic Blood Pressure When

Adminisitered Percutaneously at Different Si tes

-15

-10

-5

0

5

0 50 100 150 200

ChangeinMeanSBP(mm

Hg)

Forehead

Chest

Ankle

PHYSIOLOGICAL FACTORS


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PHYSICOCHEMICAL FACTORS

1. Skin hydration

- important as it usually promotes permeation

- principle factor

- Rank order:

- occlusive film

- ointment

- creams


2. Temperature and pH

- diffusion depends on temperature (directrelationship).

- pH- Partition theory applies i.e nonionicmolecules is more permeable than ionic

- Stratum corneum, pH = 4.5 6- How pH affect drug penetration???


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3. Drug concentration

- obeys Ficks law

dQ/dt = KDC/h

4. Partition coefficient

- also obeys Ficks law

- moderate value (Why????)

5. Diffusion coefficient

6. Molecular size

- absorption should be inversely proportion tosize (M.Wt.)

Topical dosage formsOintments

Creams

Pastes

Gels/jellies

SolutionPlasters

Aerosols

Powders


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FORMULATION OF SEMISOLID

DOSAGE FORMS1- INGREDIENTS USED IN PREPARATION OFSEMISOLIDS:

Ingredients used for formulating semisolids include :-

-Active pharamaceutical ingredient API ,

-Bases,

-Antimicrobial preservative ,

-Humectants ,

-Fragrances,

-Emulsifier

-Gelling agent,-Permeation enhancer

INGREDIENTS USED IN PREPARATION OF SEMISOLIDS1.1. ACTIVE PHARMACEUTICAL INGREDIENTS, API

Disease treated API

Warts (Keratolytic) Salicylic acid

Acne Sulphur, resorcinol

Antipruritic Benzocain, menthol

Emollient lanolin

Anti-inflammatory corticosteroid

Antifungal Benzoic acid


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http://www.inmagine.com/cr15205/cr15205016-photohttp://upload.wikimedia.org/wikipedia/commons/6/6e/Wart_filiform_eyelid.jpg


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Ointments

An ointment is a viscous semisolid preparation used

topically on a variety of body surfaces. These include

the skin and the mucus membranes of the eye (an eye

ointment), vagina, anus, and nose.

An ointment may or may not be medicated.

Typically used as:

Emollients to make skin more pliable

Protective barriers

Vehicles in which to incorporate medication

Ointment

1.2. Ointment BasesSemisolid bases do not only act as the carriers of themedicaments, but they also control the extent of absorption ofmedicaments incorporated therin .

An ointment base should be compatible with skin, stable,smooth, non-irritating, non-sensitizing, inert, capable ofabsorbing water or other liquid preparations, and of releasingthe incorporated medicament, readily .

A base for ophthalmic semisolids must be non-irritating to theeye, and It should also be sterilizable conveniently.


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INGREDIENTS USED IN PREPARATION OF SEMISOLIDS(CONT(.

ointment bases

Appropriate Selection of Ointment Base:Selection of ointment base depends on the following :

1-Desired release rate of the drug substance from theointment base .

2-Rate and extent of topical or percutaneous drugabsorption .

3-Desirability of occlusion of moisture from skin .

4-Stability of the drug in the ointment base .

5-Effect of drug on the consistency of base .

6-Easy removal of base on washing .7-Characteristic of the surface to which it is applied .

INGREDIENTS USED IN PREPARATION OFSEMISOLIDS (CONT(.

ointment bases

Ointment bases may be classified in severalways but the following classification based oncomposition is generally used which are asfollow ,

A) Oleaginous (hydrocarbon) bases .

B) Absorption bases .C) Emulsion bases .

D) Water soluble bases .


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A) Oleaginous )hydrocarbon) bases:

This is a purified mix of liquid, semi-solid orsolid hydrocarbons from petroleum

Most of the early ointment bases used to beexclusively oleaginous in nature but nowadaysthe materials obtained from plant, animal, aswell as synthetic origin are employed asoleaginous ointment bases.

Combinations of these materials can produce awide range of melting points and viscosities .

Ointment basesA) Oleaginous (hydrocarbon) bases- :These bases are:

- Immiscible with water (they are difficult to wash off)

- Not absorbed by the skin, remain on the skin forprolonged period of time without drying out

- Absorb very little water from formulation or fromskin exudates.

- Inhibit water loss from the skin by forming a waterproof film (OCCLUSIVE DRESSING).

- Improving hydration, may encourage penetration ofthe medication through skin.

Examples: Vaseline, hard paraffin, liquid paraffin,white ointment

Uses: protectants, emollient, and vehicle for soliddrugs
http://en.wikipedia.org/wiki/File:White_Petrolatum1.jpghttp://www.inmagine.com/cr15205/cr15205012-photohttp://en.wikipedia.org/wiki/File:White_Petrolatum1.jpg


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Occlusive and skin hydration

B) Absorption(Emulsifiable) Bases:

They are called as emulsifiable bases because

they initially contain no water but are capable of

taking it up to yield W/O and O/W emulsions .

Absorption bases are mostly W/O typeemulsions and have capacity to absorb

considerable quantities of water or aqueous

solution without marked changes in consistency .


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Ointment basesAbsorption bases are:

- less occlusive than the hydrocarbon bases.

- Incorporation of aqueous solution is possible.

- easier to spread.

- good emollients

- They hydrate the stratum corneum.

- Not easily removed from the skin with water

washing (external phase is oleaginous)

- Uses: protectants, emollient, and vehicle foraqueous solutions and solid drugs

Ointment bases (cont.)Absorption base (cont.)Lanolin, anhydrous lanolin, wool fat, woolwax (obtained from wool of sheep)

This is a type of wax- like that can absorb about 50%of its weight of water and is used in ointments inwhich the proportion of aqueous fluid is too large forincorporation into a hydrocarbon base.

- Wool fat is a major constituent of Simple OintmentBP

Other examples: hydrous lanolin, bees wax andcholesterol (they are added to some ointment bases toincrease their water-absorbing power)


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Ointment bases (cont.)

(C) Emulsion Bases:

They are either w/o or o/w

Hydrophilic Ointment USP

Cold cream: W/O emulsions, emollient, cleansing, not

water washable, non occlusive, shiny appearance, not

need glycerin.Vanishing cream: O/W emulsion contains large % ofwater and humectant. An excess of stearic acid in theformula helps to form a thin film when the waterevaporates.


Properties of Emulsion bases:

Water-washable, easier to remove

Non/less greasy

Can be diluted with water

Non/less occlusive

Better cosmetic appearance

Better compliance; Patients prefer cream to anointment because the cream spreads more readily,less greasy, evaporating water soothes the inflamedtissue.

Uses: Cleansing creams, emollients and vehicle forsolid and liquid drugs.


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INGREDIENTS USED IN PREPARATION OF SEMISOLIDS (CONT).

Ointment bases

D) Water Soluble Bases:

Water soluble and water washable

greaseless,

Because they soften with the addition of water,

large amounts of aqueous solutions are not

effectively incorporated into these bases.

Uses: drug vehicle


D) Water Soluble BasesThe water-soluble bases have the advantages of

being:

- Water soluble and washable- Non-greasy, non-staining

- Non/less occlusive

- Lipid free- Relatively inert

- Does not support mold growth

- Little hydrolysis, stable

-Disadvantages:May dehydrate skin and hinderpercutaneous absorption.


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The macrogols (carbowax) aremixtures of poly-condensationproducts ofethylene oxide and waterand they are described by theiraverage molecular weights (viscousliquids to waxy solids).

Different grades of cabowaxes areavailable which are designated by a

number roughly representing theiraverage molecular weights e.g.-PEG 200, PEG 400, PEG1000,PEG1540 and PEG6000.


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A general rule is that:

For wet lesions the patient should use

an aqueous dressing,

For dry skin a lipophilic base is best.

ANTIMICROBIAL PRESERVATIVES:

Some base, although, resist microbial attack but

because of their high water content, it require an

antimicrobial preservative. Commonly used

preservatives include Methyl hydroxybenzoate,

Propyl- hydroxybenzoate, Chlorocresol, Benzoicacid, Phenyl mercuric nitrate, Benzalkonium

chloride, Chlorhexidine acetate, Benzyl alcohol

and Mercurial .


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INGREDIENTS USED IN PREPARATION OF

SEMISOLIDS (CONT.)

ANTIOXIDANTS:

Example of commonly used antioxidants includeButylated hydroxy anisole, Butylated hydroxy toluene .

HUMECTANTS:

Example of commonly used humectants includesPoly Ethylene Glycol, Glycerol or Sorbitol is added ashumectants .

FRAGRANCES:

Examples of widely use fragrances are Lavender oil,

Rose oil, Lemon oil, Almond oil .

METHODS OF PREPARATION

1- BY TRITURATION:(incorporation).

When base contain soft fats and oils ormedicament is insoluble or liquid, then thismethod is usewith spatula or mortar and pestle.

2- BY FUSION:

Used for large quantities or for ointments inwhich waxes or solids of high melting points areto be mixed with semisolid or oils. Constituentsare melted successively in decreasing order ofmelting point.

3- BY OINTMENT MILLS:

It is used for large scale production where triple


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Requirement for ointments

Microbial content: do not need to besterile, but must meet the FDArequirement of the test for absence ofbacteria such as S. areus and P.aeruginosa for dermatologicalproducts.

Packaging, storage, labeling: (labelshould include the type of base used)

Additional standards: viscosity, invitro release

CREAM

Semisolid preparations containing one ormore medicinal agents dissolved in eitheran o/w or w/o emulsion or in another typeof water-washable base.

Typically of low viscosity, two phasesystem (w/o or o/w)

Appears creamy white due to thescattering of light.

Traditionally, it is the w/o cold cream

Currently and most commonly, it is the o/wemulsion.


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Creams as drug delivery systems

Good patient acceptance

Water evaporation concentrates drug on skin

surface

Examples;

Vanishing cream: o/w with high % of water and stearic

acid.

Cold cream: (an emulsion for softening and cleansing the

skin): w/o, white wax, spermaceti, almond oil, sodiumborate.

CREAM

EMULSIFIER:

Important in creams

Ideal properties of emulsifier includes:

a) Must reduce surface tension for proper

emulsification .

b) Prevents coalescence .

c) Effective at low concentration .


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GELLING AGENTS:

Important for gel (jelly) semisolid preparations

These are organic hydrocolloids or hydrophilic

inorganic substances. They are Tragacanth,

Sodium Alginate, Pectin, Starch, Gelatin,

Cellulose Derivatives, Carbomer, and Poly Vinyl

Alcohol Clays .

There are numerous gelling agents varying ingelling ability. Commonly used gelling agents

INGREDIENTS USED IN PREPARATION OF

SEMISOLIDS (CONT).

Material % Brookfield viscosityCP

0

Carbomer 941resin NFCarbomer 941resin NF

Carbomer 941resin NFCarbomer 941resin NFSodium carboxymethyl cellulose

Guar gumMethyl cellulose

Locust bean gumSodium alginate

0.150.25

0.501.001.501.502.002.502.50

29006300

44000810005000804052002280010400

Table 4.4 : Gelling agents (6)

- Commonly used Gelling agents


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Some recent semi-solid preparation are

used via other routes of administration i.e.

other than topical route


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Recent Advances in Semisolids

1. OintmentRectal Ointment: it is used for the

symptomatic relief against anal and peri-anal

pruritus, pain and inflammation associated with

hemorrhoids, anal fissure, fistulas and proctitis .

For intrarectal use, apply the ointment with the

help of special applicator.


2. Creams

Creams containing microspheres:

Albumin microsphere containing vitamin A

can be administered by using creams

topically. These microspheres were able toremain on the skin for a long period of

time, and as a consequence they were

able to prolong the release of vitamin A.


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3. Bioadhesive gels

Gel formulations with suitable rheological

and mucoadhesive properties increase the

contact time at the site of absorption

(nasal or ocular delivery(.

E.g. Chitosan bioadhesive gel was formulated for nasaldelivery of insulin .

Bioadhesive and pH sensitivehydrogel


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4.Hydrogels

Usually made of hydrophilic polymers, which

under certain conditions and concentration,

jellify .

The polymer produces a coherent three-

dimensional net-like structure, which fixes the

liquid vehicle as the external phase. .

Intermolecular forces bind the molecules of thesolvent to a polymeric net, thus decreasing the

mobility of these molecules and producing a

structured system with increased viscosity .


Hydrogel (cont(.

Example: In peroral administration, hydrogelscan deliver drugs to four major specific sites;mouth, stomach, small intestine and colon.

By controlling their swelling properties or

bioadhesive characteristics in the presence of abiological fluid, hydrogels can be a useful devicefor releasing drugs in a controlled manner atthese desired sites .


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Hydrogel (cont(.Additionally, they can also adhere to certainspecific regions in the oral pathway, leading to alocally increased drug concentration, and thus,enhancing the drug absorption at the releasesite.

Example: Oral anesthetic gel for the temporaryrelief of minor irritation and pain associated with

minor dental procedures; minor irritation of themouth or stomatitis .

Recent Advances in SemisolidsThermosensitive and pH-senstive sol-gel

reversible hydrogels :

They are the aqueous polymeric solutions which

undergo reversible sol to gel transformation

under the influence of environmental conditions

like temperature and pH which result in in situ

hydrogel formation .


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Thermosensitive sol-gel reversible hydrogels(cont .(Example; The goal of oral insulin delivery devices is toprotect the sensitive drug from proteolytic degradation inthe stomach and upper portion of the small intestine .Theuse of pH-responsive, poly (methacrylic-g-ethyleneglycol) hydrogels as oral delivery vehicles for insulinwere evaluated .

In the acidic environment of the stomach, the gels wereunswollen due to the formation of intermolecular polymer

complexes. Insulin remained in the gel and wasprotected from proteolytic degradation .

In the basic environment of the intestine, the complexesdissociated which resulted in rapid gel swelling andinsulin release

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Semisolid Course 2