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SEMISOLID DOSAGE FORM

Contributed by Sanjay J Daharwal

Novel Approches about Semisolid Dosage Forms

The new access in semisolid dosage forms by adding or applying some new approaches to improve them from
bioavailability, efficacy, drug dosing cost etc and also techniques which may be launched recently, but not widely used.

Article developed by S. J. Daharwal, Ekta Verma and R. B. Saudagar

Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur

SEMISOLID DOSAGE FORMS:

Semisolids constitute a significant proportion of pharmaceutical dosage forms They serve as carriers for drugs that are
topically delivered by way of the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and
external ear lining, A wide range of raw materials is available for the preparation of a semisolid dosage form. Apart from
the usual pharmaceutical ingredients such as preservatives, antioxidants, and solubilizers, the basic constituents of a
semisolid dosage form are unique to its composition the choice of suitable raw materials for a formulation development is
made on the basis of the drug delivery requirements and the particular need to impart sufficient emolliency or other quasi-
medicinal qualities in the formulation. Because of their peculiar theological behavior, semisolids can adhere to the
application surface for sufficiently long periods before they are washed off. This property helps prolong drug delivery at
the application site. A semisolid dosage form is advantageous in terms of its easy application, rapid formulation, and
ability to topically deliver a wide variety of drug molecules. Semisolid dosage forms usually are intended for localized
drug delivery. In the past few years, however, these forms also have been explored for the systemic delivery of various
drug

Ointments: are semisolid preparations for external application to skin or mucous membranes. Their composition softens
but does not melt upon application to the skin. Therapeutically, ointments function as skin protective and emollients, but
they are used primarily as vehicles for the topical application of drug substances.

Creams: are semisolid dosage forms that contain one or more drug substancesDissolved or dispersed in a suitable base,
usually oil in- water emulsion or aqueous microcrystalline dispersion oflong-chain fatty acids or alcohols that are water-
washable and are cosmetically and aesthetically acceptable.

Gels: are semisolid systems that consist of either suspensions of small inorganic particles or large organic molecules
interpenetrated by a liquid.Gels can be either water based (aqueous gels) or organic solvent based (organogels).

Pastes: are semisolid dosage forms that contain one or more drug substances incorporated in a base with large
proportions of finely dispersed solids, are intended for external application to skin, but very thick & stiff.

Jellies: are transparent, non-greasy, semisolid prepration for external applications to skin & mucous membrane.

Poultices: are soft, viscous wet masses of solid substances applied to skin & now outdated.
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Suppositories: are intended in other than oral cavity i.e., vaginal, nasal cavity. generally introduced in systemic.

Percutaneous drug absorption: Semisolid dosage forms for dermatological drug therapy are intended to produce desired
action at specific sites in the epidermal tissue. A drug’s ability to penetrate the skin’s epidermis, dermis
and subcutaneous fat layers depends on the properties of the drug and the carrier base. Although drug and the carrier
base. Although drug and the carrier base. Although area for most dermatological disorders lies in the viable epidermis or
upper dermis. Hence, a drug’s diffusive penetration of the skin — percutaneous absorption— is an
important aspect of drug therapy. The main portals of drug entry are the follicular region, the sweat ducts or the unbroken
stratum corneum between the appendages. A substance’s particular route mainly depends on the
physicochemical properties of the drug and the condition of the skin.

Advances in the formulation of semisolid dosage forms

The formulation of a suitable semisolid dosage form involves the selection of an appropriate drug carrier system, with a
special emphasis on the drug’s physicochemical properties and required therapeutic application. Drug delivery by
means of semisolid dosage forms has seen new challenges in the past few years in terms of altered drug-release profiles
as well as the enhanced stability of active p dosage forms has seen new challenges harmaceutical ingredients (APIs).

Systemic drug delivery: The skin’s large surface area1.73 m2, facilitates its use as a potential site for the
application of topical dosage forms .With this method, not only can some therapeutically active agents be delivered
transdermally with ease, but first-pass gut and hepatic metabolism is avoided, constant drug levels in the bloodstream
are maintained for longer periods of time, potential side effects are decreased, bioavailability is improved, the dosage is
smaller, patient compliance is increased and drug termination in problematic cases is facilitated as compared with other
routes of drug administration is improved, the dosage is smaller, patient compliance is increased stration Semisolid and
drug termination in problematic cases is facilitated dosage forms have proven to be ideal carriers for this purpose and
several novel developments in their formulation technologies have emerged in recent years. In addition to the use of
penetration enhancers alone, their combination with cosolvents that deliver a drug solubilized form has led to the
achievement of higher drug permeability.

Submicron emulsion vehicle system. Conventional creams have a mean droplet size ranging from 10 to100 m. Such
formulations have demonstrated poor penetration of drug-loaded oil droplets into deep skin layers. It has been reported
that microparticles with diameters penetrate follicular ducts, whereas penetrate follicular ducts, whereas particles 10 m
remain on the skin surface, and those 3 m are distributed randomly into hair follicles and stratum corneum .Taking these
constraints into consideration, researchers have developed the submicron emulsion vehicle system (SMEVS) for
improving drug permeation. The submicron lipid particles of an SMEVS penetrate the layers of the stratum corneum,
increasing its fluidity and leading to the disruption of barrier continuity. Significant hydration of the stratum corneum,
assisted by gap formation, permits the penetration of submicron emulsion particles by forming a drug depot in the skin.
The result is slow, continuous, and controlled systemic delivery of the drug. An SMEVS can be formulated by processing
a medium-chain triglyceride emulsion with a high pressure homogenizer. In addition, the presence of lecithin, an efficient
dispersing agent, causes a drastic reduction in droplet size, usually to between 100 and 300 nm.

Gels with permeation enhancers. Skin can act as a barrier to the deeper penetration of drug molecules. With the
introduction of various penetration enhancers, however, systemic drug delivery through the transdermal route has gained
major footing. These chemicals, incorporated in a suitable drug-carrying semisolid vehicle, enhance the amount of drug
permeation through skin. The high diffusion rates of indomethacin and diclofenac show that lecithin microemulsion gel is
a suitable matrix for transdermal drug delivery.

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Localized drug delivery. Localized drug delivery by semisolid dosage forms continues to be a major area of research.
Advances in formulation approaches have led to increased drug stability as well as improvement in the aesthetic appeal
of semisolid dosage forms.

Oleo-hydrogel systems. Oleo- hydrogel systems for localized skin have been explored successfully. Rhee et al.
examined transdermal permeation using various vehicle systems to avoid systemic side effects and gastrointestinal
irritation from ketoprofen upon oral administration. The researchers examined an oleo-hydrogel system that consisted of
ketoprofen incorporated into an emulsion of oil and carbomer hydrogel mixture, with N-methylpyrrolidone as a
permeation enhancer. The greater bioavailability of ketoprofen in the oleo-hydrogel system was ascribed to good
drugrelease properties, higher emulsion droplet stability of the carbomer gel, and the penetration-enhancing effect of
Nmethylpyrrolidone. The formulation of ketoprofen oleohydrogel that showed maximum percutaneous absorption was
one that contained 3% ketoprofen, 1% carbomer, 10% Nmethylpyrrolidone, 10% oils, 8% surfactant, and water adjusted
to pH 4.6 using triethanolamine.

Volatile vehicle–antinucleant polymer systems. Studies have investigated various techniques to enhance the
transdermal permeation of topically applied drug molecules. Increasing the thermodynamic activity of drug molecules
was found to be the most efficient approach. This increase can be achieved by the volatile vehicle–antinucleant
polymer system Enhanced permeation of sodium nonivamide acetate (an antinociceptive agent) was observed with
ethanol–buffer solutions (pH 4.2) containing antinucleant polymers. The system used supersaturation (achieved
by evaporation of the vehicle) for penetration enhancement. In supersaturated solutions the drug is in a high state of
activity and has a great leaving tendency, resulting in increased flux.

Lecithin microemulsion gel. Lecithin microemulsion gel is a promising matrix system for transdermal drug delivery
.Microemulsion gels are obtained by dispersing soybean lecithin (a mixture of phosphatidyl cholines) in a nonpolar
organic solvent, thereby forming an entangled network of long and flexible multimolecular aggregates. Fatty-acid esters
such as isopropyl palmitate are preferred organic solvents because of their relatively high viscosity and complete optical
transparency.

Cream containing lipid nanoparticles. For enhanced penetration of topical drugs, occlusion of skin is the prime criterion.
This requirement can be achieved easily by the incorporation of large quantities of fats and oils, especially liquid and
semisolid paraffin. However, such formulations have the limitations of poorcosmetic properties characterized by a greasy
feel and glossy appearance.The development of a water-in-oil cream wherein the aqueous phase was divided into small
droplets solved this problem.

Solid lipid nanoparticles. Solid lipid nanoparticles of glyceryl behenate have been investigated as efficient carrier systems
for topical use . They provide both burst and sustained drug release. Burst release improves the penetration of drug into
the skin. Solid lipid nanoparticles possess the advantages of better drug penetration because the small particle size of
their drug-carrier system ensures close contact to the stratum corneum and increases the amount of encapsulated drug
penetrating the skin.

Liposomes as drug carriers. Liposomes have shown great potential as novel drug carriers for dermal and transdermal
systems. Liposomes are microscopic vesicles composed of membrane-like lipid layers surrounding an aqueous
compartment They also serve as a reservoir for the prolonged release of drugs within various skinlayers , thereby
reducing the rapid elimination of drug into the blood or lymphatic circulation.

MACHINES USED IN MANUFACTURING OF SEMISOLID DOSAGE FORM:

SIZE REDUCTION APPARATUS

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1. Morter and pestle

2. Hammer mill

3. Ball mill

4. Colloid mill

MIXING EQUIPMENTS

1. Agitator mixers: sigma mixers and planetary

2. Shear mixers: triple roller mill and collidal mill

CENTRIFUGATION APPARATUS

1. Conical disc centrifuge or De laval clarifier

2. Supercentrifuge

EVALUATION PARAMETER:SEMISOLID TOPICAL DOSAGE FORMS

Semisolid topical dosage forms include creams, ointments, and gels. In vitro drug release from semisolid topical dosage
forms has been extensively investigated using the Franz cell diffusion system, with a synthetic membrane and to some
extent using the enhancer cell.Depending on the solubility of the drug substance, the receptor medium may need to
contain alcohol and/or surfactant. Deaeration is critical to avoid bubble formation at the interface with the membrane. A
synthetic membrane often serves as an inert support membrane. Depending on the characteristics of the drug product, it
may also be possible to conduct the in vitro test without a synthetic support membrane. As with transdermal products, the
test temperature is typically set at 32°C to reflect the usual skin temperature. Deviations might be justified when products
are for specific sites of action; for example, vaginal creams may be tested at 37°C. No compendial apparatus, procedures,
or requirements for in vitro release testing of semisolid topical dosage forms have been described in relevant
pharmacopeias to date. However, the FDA's Guidance for Industry on Scale Up and Post Approval Changes for
Semisolid (SUPAC-SS) dosage forms describes the release rate studies using the vertical diffusion cell (Franz cell)
procedure and requires in vitro release rate comparison between prechange and postchange products for approval of
SUPAC-related changes.Because of the value and importance of release rate, it is highly desirable to determine the
release data of semisolid dosage forms. There is also a need to develop compendial test method(s). It is expected that
given the variety of formulations, sites of applications, and release rates for semisolid topical dosage forms, no single test
procedure would be suitable for the development, biopharmaceutical characterization, and quality control of all semisolid
topical dosage forms.

TRANSDERMAL PATCHES

Although several apparatus and procedures have been used to study in vitro release characteristics of transdermal
patches, it is desirable to avoid unnecessary proliferation of dissolution test equipment. Current compendial apparatus
include the paddle over disk/disk assembly method (USP apparatus 5/PhEur 2.9.4.1), the rotating cylinder (USP
apparatus 6/PhEur 2.9.4.3), the reciprocating disk (USP apparatus 7), and a paddle over extraction cell method (PhEur
2.9.4.2).The paddle over disk procedure with a watch glass-patch-screen sandwich assembly is considered to be the
method of choice, as it has been shown experimentally that this procedure results in almost the same release profile as
other, more complicated apparatus for all US-marketed transdermal patches.The PhEur considers 100 rpm a typical
agitation rate and also allows for testing an aliquot patch section. pH of the medium ideally should be adjusted to pH 5 to
6, reflecting physiological skin conditions. For the same reason, the test temperature is typically set at 32°C (even though
the temperature may be higher when skin is covered). The latter may be an appropriate means of attaining sink
conditions, provided that cutting a piece of the patch is validated to have no impact on the release mechanism.

ADVANTAGES OF NOVEL APPROACHES:

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- Carriers like liposomes delivers drug in to the dermal & transdermal systems & retained for providing the prolonged
release of drugs.

- SLN provide sustained drug release also better penetration of drugs because the small particle size of their drug-carrier
system ensures close contact to the stratum corneum and increases the amount of encapsulated drug penetrating the
skin.

- Microemulsion gels are used for systemic drug delivery. i.e., lecithin microemulsion gel.

- Ethosomes, cubosomes are used for cosmetics due to their better penetration in the stratum corneum.

- iontophoresis, electoporation and phonosoresis are used to deliver ionic drugs, in systemic circulation.

- oleo-hydrogel used for local action to avoid systemic side effects.

DISADVANTAGES :

- Their production cost is high.

- Not available easily.

- Generally low efficacy.

So, novel approaches of semisolid dosage form can be classified according to there approaches:

a.) BIOLOGICAL MEANS

1. NANOPARTICLES USED IN DERMAL APPLICATION

Nanoparticulate systems able to control release and to improve targeting to skin are innovative common topics both in
pharmaceutical and cosmetic field. Liposomes are of course the best known nanoparticulate systems. Several studies
demonstrated their efficacy as drug delivery systems for topical administration ways The well characterized liposome
vesicles can host different molecules in the bilayer, on the surface or in the inner of their structure. Since liposome
composition and structure strictly resemble to the stratum corneum, percutaneous administration of this vehicle leads to
deposition of lipidic components from which liposome load can be slowly release. As an alternative to liposome, solid
lipid nanoparticles (SLN) represent innovative drug carrier systems firstly designed for i.v. administration and recently
investigated for transdermal application. Many studies have been demonstrated the efficiency of liposomes as drug
carriers for different administration ways. Nevertheless liposomes are characterized by some drawbacks such as the
limited physical stability. Recently some alternative nanodispersed systems have been developed, such as SLN,
Ethosomes and cubosomes. SLN possess interesting features as nanotechnology systems for a wide spectrum of
application. Their solid matrix allows protection of chemically labile agents from degradation. The use of SLN in
dermatics seems very attractive due to the lipophilic character of their components improved skin hydration is conferred
due to adhesive and coherent film formation exherting occlusive properties. Moreover, SLN may also enhance the effects
of active compounds in cosmetics. Ethosomes are attracting systems able to solubilize different kind of molecules and to
enhance their delivery through the skin due to the presence of ethanol. Moreover their physical stability improves their
use with respect to liposomes. Bicontinuous cubic liquid crystalline phases, either in bulk or cubosome form, offer unique
properties of particular interest to the personal care industry. Cubic phase materials can be formed by simple
combination of biologically compatible lipids and water and are thus well-suited for use in treatments of skin, hair, and
other body tissue. Dermal application of personal care products containing cubosomes is particularly interesting due to
the possible stratum corneum-cubosome interaction recently demonstrated.

2. LIPOSOMES

Liposomes were discovered in the early 1960’s and subsequently studied as cell membrane models. They have
since gained recognition in the field of drug delivery. The particle size of liposomes ranges from 20 nm to 10 μm in
diameter. Liposomes vary in charge and in size depending on their manufacturing protocol and type of (phospho) lipid
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bilayer used (the small unilamellar vesicle [SUV] size range is 0.02 -0.05 μm, the large unilamellar vesicles [LUV]
size range is greater than 0.06 μm and the multilamellar vesicle [MLV] size range is 0.1 – 0.5 µm). The
physicochemical characteristics of the liposomes, like particle size, lamellarity, surface charge, sensitivity of pH changes
and bilayer rigidity can be manipulated. Liposomes showed promising result in the drug delivery but their applicability is
limited primarily to specific use because of short half-life in blood circulation. The circulation time of liposomes in the
blood stream is dramatically increased by attaching polyethylene glycol (PEG) units to the bilayer, known as long
circulating (Stealth) liposomes.Physical methods such as iontophoresis, ultrasound, and tape-stripping can further assist
the delivery of drugs encapsulated in liposomes. Recent breakthroughs with liposomes are beneficial to topically applied
permeants, especially for dermatological medications, cosmetic ingredients, and protein/peptide macromolecules. The
current review emphasizes the potential of various novel drug delivery strategies like liposomes, niosomes, aspasomes,
microsponges, microemulsions, hydrogels proniosome gel formulations, and solid lipid nanoparticles in optimizing and
enhancing the topical delivery of antiacne agents. it may be concluded from the study that complex lipid molecules,
transfersomes, can increase the transdermal flux, prolong the release, and improve the site specificity of bioactive
molecules.

b.)PHYSICAL MEANS:

1. PHONOSORESIS(SONOPHORESIS):

It is defined as the movement of drugs through intact skin & underlying soft tissues under the influence of an ultrasonic
perturbation. It is safe technique for enhancing drug administration & is effective in clinical applications when with a
proper frequency, power level, and duration. It increases drug permeation through the skin by disordering the structured
lipids in the stratum corneum. Applications of low-frequency (20 KHz) ultrasound enhances transdermal transport of high-
molecular weight proteins. Ultrasound based on hypothesis that if cavitation plays an important role in ultrasound-
facilitated skin permeation, & since the cavitation threshold (i.e., the minimal ultrasound intensity required to cause
cavitation) increases rapidly with an increase of ultrasound frequency’ lower frequency would cause more
cavitation and hence, higher skin Permeation of a drug. Many conventional sonophoresis devices have been developed
and they are categorized into basic types, namely the disk-type and the horn-type.Ultrasonic energy delivered from
devices is being used to enhance therapeutic efficacy in the treatment of local conditions by a process of phonosoresis
and sonosoresis. Current research is applied on synergistic or additive effect. In addition, a sample of interstitial fluid or
its components may be extracted through permeabilized skin for diagnostic applications.

2. IONTOPHORESIS

There has been a growing awareness in recent years of potential therapeutic importance of achieving true controlled
drug delivery where the rate of drug output may be modulated in a precisely controlled manner. Transdermal drug
delivery has usefulness in achieving the controlled delivery of pharmaceuticals, which are relatively small in molecular
size and rather lipophilic in nature, however, these systems are rather limited in their capability of achieving the
transdermal systemic delivery of peptides, proteins and drugs which is often charged and highly hydrophilic in nature. In
order to deliver an ionic drug, peptide/protein molecule through transdermal delivery to attain a systemic effect, and
chemical and/or physical methods is required to enhance the rate of penetration of therapeutic agent through the main
diffusion barrier. The intophoratic technique is highly desirable to improve the transdermal delivery of peptide and
proteins using a lower current intensity with a short time period. The idea of applying electric current to increase the
penetration of electrically charged drugs into surface tissues was probably organized by Veratti in 1947. Leduc did the
first well-documented experiments at the beginning of the 20th century. Leduc demonstrated the introduction of
strychnine and cyanide ions into the rabbits when the correct polarities were applied. By the process of electromigration
and electro-osmosis, iontophoresis increases the permeation of charged and neutral compounds, and offers the option
for programmed drug delivery. Interest in this field of research has led to the successful delivery of both low (lidocaine)
and high molecular drugs, such as peptides (e.g., luteinising hormone releasing hormone, nafarelin and insulin).
Combinations of iontophoresis with chemical enhancers, electroporation and sonophoresis have been tested in order to
further increase transdermal drug permeation and decrease possible side effects. In addition, rapid progress in the fields
of microelectronics, nanotechnology and miniaturisation of devices is leading the way to more sophisticated iontophoretic
devices, allowing improved designs with better control of drug delivery.

3. ELECTROPORATION

It is a phenomenon in which the membrane of a cell exposed to high-intensity electric field pulses(up to several hundred
volts for micro- or milliseconds) can be temporarily, thus becoming highly permeable to exogenous molecules in the
surrounding media. A recent report provide a theoretical analysis according to which ,charged molecules were
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considered transporting through existing shunt routes of the skin at transdermal voltage <100 v. when transdermal
voltage was greater than 100v, the transcorneocyte pathway was also accessible to charged molecules as lipid bilayers
were electroporated.Synergistic effect was shown by ultrasound and electric field than positive of electric field only.
Research is doing for effective, safe, cost-effective, as well as powerfully versatile (e.g., microchip controlled for complex
drug delivery patterns).

c.) CHEMICAL MEANS:

Carbopol polymers are polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. They are produced
from primary polymer particles of about 0.2 to 6.0 micron average diameter. The flocculated agglomerates cannot be
broken into the ultimate particles when produced. Each particle can be viewed as a network structure of polymer chains
interconnected via cross-linking. Carbomers were first prepared and patented in 1957. Since then, a number of extended
release tablet formulations, which involve carbomer matrices, have been patented. Carbomers readily absorb water, get
hydrated and swell. In addition to its hydrophilic nature, its cross-linked structure and its essentially insolubility in water
makes Carbopol a potential candidate for use in controlled release drug delivery system. Carbopol polymers are
manufactured by cross-linking process. Depending upon the degree of cross-linking and manufacturing conditions,
various grades of Carbopol are available. Each grade is having its significance for its usefulness in pharmaceutical
dosage forms Polymers produced in co solvent (a cyclohexane / ethyl acetate mixture) have a bulk density of 176 kg/m3
(11 lbs/ft3). Polymers produced in ethyl acetate have an ash content (as potassium sulfate) of 1-3% on average.

Conclusion: Semisolids constitute a significant proportion of pharmaceutical dosage forms. It has their peculiar
theological behavior; semisolids can adhere to the application surface for sufficiently long periods before they are
washed off. The novel approaches discussed were applicable for transdermal delivery of pharmaceuticals.

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