Recent advances in formulation aspects & manufacturing of semisolids

RECENT ADVANCES IN FORMULATION ASPECTS & MANUFACTURING OF SEMISOLIDS

M.PRIYANKAM. Pharmacy 1st year

Pharmaceutics

School of Pharmaceutical Sciences, JNTUK

CONTENTS

Introduction to novel semisolids

Recent advances in semisolid dosage forms

Patented technologies in semisolids

Manufacturing of semisolids

Packaging

Storage

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DEFINITION OF SEMISOLIDS

Semisolid pharmaceutical system comprise a body of product,which when applied to skin or mucous membrane tends to alleviateor treat a pathological condition or other protection againstharmful environment or cosmetic purpose.

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INTRODUCTION TO NOVEL SEMISOLIDS

Novel semisolids are non greasy since they are made up of waterwashable bases. Hence they cause less irritation to skin and aresuperior to conventional semisolid dosage form.

Novel creams now a days are provided with nanoparticles andmicrospheres, which has an excellent emollient effect, with betterspreadability, and less staining than oleaginous ointments.However both medicated and non-medicated creams provide verygood emollient effects, oleaginous ointments are preferred for dry,chapped skin in an environment of low humidity because of itsocclusive properties.

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RECENT ADVANCES IN SEMISOLID DOSAGE FORMS

A. OINTMENTS

RECTAL OINTMENT:-

It is used for the symptomatic relief against anal and peri-anal pruritus,pain and inflammation associated with haemorrhoids, anal fissure,fistulas and proctitis

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B. CREAMS

1) CREAMS CONTAINING MICROSPHERES: -

Albumin microsphere containing vitamin A can be administered byusing creams topically. 222 ± 25 μm size of microsphere of vitamin Awere produced by emulsion method. The in vitro and in vivo drugrelease of a microencapsulated and nonmicroencapsulated vitamin Acream was studied. The in vivo study in six volunteers revealed thatthese microspheres were able to remain on the skin for a long period oftime, and as a consequence they were able to prolong the release ofvitamin A.

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2) LAMELLAR FACED CREAMS: -

They are liquid paraffin in water emulsion prepared from cetrimide/ fatty alcohol like mixed emulsifiers and ternary system formed bydispersing the mixed emulsifier in require quantity of water. Thecationic emulsifying wax showed phenomenal swelling in waterand this swelling was due to electrostatic repulsion whish can besuppressed by addition of salt and can be reduced by changingsurfactant counter ion.

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3) CREAMS CONTAINING LIPID NANOPARTICLES:-

When using oils & fats for improved penetration of topical drugs, ithave the limitations of poor cosmetic properties since they have greasyfeel and glossy appearance.

The development of a water-in-oil cream containing smallparticles of solid paraffin was studied. A high degree of occlusivity wasobtained with smooth, flexible films prepared by drying aqueousdispersions of solid paraffin particles with a mean size of 200nm(nanoparticle dispersion). However, this nanodispersion revealed arough texture when applied. The development of a water-in-oil creamwherein the aqueous phase was divided into small droplets solved thisproblem. Nanoparticles were incorporated in the aqueous phase.Hence, the oil phase in which the water droplets were dispersed servedas a lubricant for nanoparticles, thereby preventing a rough feel duringapplication.

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C. GELS

1) CONTROLLED RELEASE GELS

Gel formulations with suitable rheological and

muco-adhesive properties increase the contact

time at the site of absorption.

Gelrite gels were formed in simulated tear fluid at concentrationsof polymer as low as 0.1%, and it was shown that sodium was the mostimportant gel promoting ion in vivo.

The gels can be evaluated in the chamber using porcine nasalmucosa and from the results it was found that the rate of transport ofdrugs through the mucosa could be controlled by the rate of release fromthe formulation.

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2) ORGANOGELSSorbitan monostearate, a hydrophobic non-ionic surfactant, gels anumber of organic solvents such as hexadecane, isopropyl myristate,and a range of vegetable oils. Gelation is achieved bydissolving/dispersing the organogelator in hot solvent to produce anorganic solution/dispersion, which, on cooling sets to the gel state.Cooling the solution/dispersion causes a decrease in the solvent gelatoraffinities, such that at the gelation temperature, the surfactantmolecules self-assemble into toroidal inverse vesicles. Further coolingresults in the conversion of the toroids into rod-shaped tubules. isformed which immobilizes the solvent. An organogel is thus formed.

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3) EXTENDED RELEASE GELS

TIMERx is a controlled release technology consists of anagglomerated, hydrophilic complex that, when compressed, forms acontrolled-release matrix.

Advantage of this system includes,

a) Predictable modified release profile like zero order or first order orinitial immediate release kinetics

b) It can be manufacture on standard manufacturing equipment.

c) Cheap.

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4) AMPHIPHILIC GELS

Amphiphilic gels can prepared by mixing the solid gelator likesorbitan monostearate or sorbitan monopalmitate and the liquid phaselike liquid sorbitan esters or polysorbate and heating them at 60°C toform a clear isotropic sol phase, and cooling the sol phase to form anopaque semisolid at room temperature

Amphiphilic gel microstructures consisted mainly of clusters oftubules of gelator molecules that had aggregated upon cooling of the solphase, forming a 3D network throughout the continuous phase. The gelsdemonstrated thermoreversibility. Gelation temperature and viscosityincreased with increasing gelator concentration, indicating a morerobust gel network.

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At temperatures near the skin surface temperature, the gels softenedconsiderably; this would allow topical application. This study hasdemonstrated the formation/preparation of stable, thermoreversible,thixtropic surfactant gels (amphiphilogels) with suitable physicalproperties for topical use

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5) HYDROPHILIC GELS:-

This system composed of the internal phase made of a polymer producinga coherent three-dimensional net-like structure, which fixes the liquidvehicle as the external phase. Intermolecular forces bind the molecules ofthe solvent to a polymeric net, thus decreasing the mobility of thesemolecules and producing a structured system with increased viscosity.

The physical and chemical bonds binding the particles of theinternal phase provide a relatively stable structure, which can originate byswelling of solid polymers, or by decreasing the solubility of the polymerin a solution

This dosage form seems to be prospective for the development ofmodern drugs based on systems with prolonged and controlled release ofactive ingredients.

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6) NON AQUEOUS GELS:-

Ethyl cellulose was successfully formulated as a non-aqueous gel withpropylene glycol dicaprylate/dicaprate. The novel non-aqueous gelexhibited rheological profiles corresponding to a physically cross-linkedthree dimensional gel network, with suitable mechanical characteristicsfor use as a vehicle for topical drug delivery. Molecular conformation ofthe solvent was found to influence the molecular interactions associatedwith formation of ethylcellulose gel networks.

7) BIOADHESIVE GELS:-

Chitosan bio-adhesive gel was formulated for nasal delivery of insulin.Drug release was studied by a membraneless diffusion method and bio-adhesion by a modified tensiometry test

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8) THERMOSENSITIVE SOL-GEL REVERSIBLE HYDROGEL:-

They are the aqueous polymeric solutions which undergo reversible solto gel transformation under the influence of environmental conditionslike temperature and pH which results in insitu hydrogel formation.

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ADVANTAGES:-

a) It is easy to mix pharmaceutical solution rather than semisolids

b) Biocompatibility with biological systems

c) Convenient to administer

d) The pharmaceutical and biomedical uses of such sol-gel transitioninclude solubilisation of low molecular weight hydrophobic drugs

e) Release can be in a controlled fashion.

f) Helps to deliver labile bio-macromolecule such as proteins andgenes.

g) Immobilization of cells

h) And tissue engineering .

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9) COMPLEXATION GELS:-

The goal of oral insulin delivery devices is to protect the sensitive drugfrom proteolytic degradation in the stomach and upper portion of thesmall intestine. In this work, the use of pH-responsive, poly hydrogels asoral delivery vehicles for insulin were evaluated

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PATENTED TECHNOLOGIES IN SEMISOLIDS1) DELIVERY OF MONOCLONAL ANTIBODY USING SEMISOLID

DOSAGE FORM:-

Lysostaphin was formulated into a hydrophilic cream that forms anemulsion with the secretions of the nasal mucosa, and aqueousformulations were made containing the muco-adhesive polymerspolystyrene sulfonate and chitosan. Intranasal pharmacokinetics of thedrugs was measured in mice and cotton rats. Lysostaphin formulated inthe cream increased nasal retention of the drug as compared tolysostaphin in saline drops

The results demonstrate that cream and polymer delivery systemssignificantly decrease the clearance rate of lysostaphin from the nose,thereby enhancing their therapeutic potential for eradicating S. aureusnasal colonization.

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2) TOPICAL DELIVERY OF VITAMIN A

Immediate release & sustained release of vitamin A can be obtained byusing SLN suspensions. For dermal application burst release and sustainrelease are taken into consideration. Burst release can be useful toimprove the penetration of a drug. Sustained release becomes importantwith active ingredients that are irritating at high concentrations or tosupply the skin over a prolonged period of time with a drug.

Glyceryl behenate solid lipid nanoparticle(SLN) were loaded withvitamin A and the release profiles were studied. Franz diffusion cellswere used to assess the release kinetic over a period of 24 h. Within thefirst few hours SLN displayed controlled release. After longer periods oftime, the release rate increased and even exceeded the release rate ofcomparable nanoemulsions.

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3) DELIVERY OF EPIDERMAL FACTOR BY TOPICAL ROUTE

Topical treatment of recombinant human epidermal growthfactor(rhEGF) ointment promotes wound healing by increasing the rateof epidermal proliferation & accelerating the level of wound contractionrelated to myofibroblast proliferation & collagen deposition

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4) TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN

There are an ever increasing number of agents that can be used to helppatients with neuropathic based oral & perioral pain problems. A clearadvancement in the delivery of such medications is the development ofa vehicle-carrier agent, that can penetrate the mucosa & cutaneoustissues & carry the active medication with it to the treatment site.

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5) FOAM DRUG DELIVERY

Pharmaceutical foams are pressurized dosage forms

containing one or more active ingredients that,

upon valve actuation, emit a fine dispersion of

liquid and/or solid materials in a gaseous medium.

Foam formulations are,

a) Generally easier to apply

b) Less dense

c) Spread more easily than other topical dosage forms

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MANUFACTURING OF SEMISOLIDS

• Trituration method

• Fusion method

• Emulsification method

• Chemical reaction method

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A. TRITURATION METHOD

Size reduction Levigationmixing with base triturationmixingbase to produce final weight homogenisation filling

B. FUSION METHOD

The ingredients of the base are melted together & properly mixed toobtain a uniform product

On small scale, fusion method is carried out in a porcelain dish, whichis placed in a water bath

Initially the ingredients of the base are added in the decreasing order oftheir melting points & melted with constant stirring

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Melt lipid in order of mix oil phase under

increasing melting point agitation mixing cooling

thermostable solid filling

ingredients

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C. EMULSIFICATION METHOD

Steps involved in this method are

• Preparation of oil & aqueous phases

• Mixing of the phases

• cooling the emulsion

• HomogenizationOil phase mixing of phases

Melt lipid in order of under slow agitation Emulsified Cooling

Increasing melting point

Homogenization

Aqueous phase

Mixing aqueous phase Fillingwith emulsifier heat to dissolve at 70o C

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D. CHEMICAL REACTION METHOD

In this product is formed by chemical reaction, which involves bothfusion & mechanical mixing.

Eg:- Iodine ointment

PROCEDURE:-

Powder iodine is taken in a mortar & pestle & add it to Arachis oiltaken in a flask

Heat the mixture to 50oC with occasional stirring until greenish blackcolour appears

Add yellow soft paraffin to the above mixture & heat it to 40o C withmixing

Cool the ointment

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EQUIPMENTS USED FOR THE MIXING OF PHASES

• AGITATOR MIXERS

Eg:- sigma mixer

planetary mixer

• SHEAR MIXERS

Eg:-triple roller mill

colloidal mill

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PACKAGING OF NOVEL SEMISOLIDSThe specific FDA regulation pertaining to drug products state that“container closures & other component part of drug packages, to besuitable for that intended use must not be reactive, additive orabsorptive to the extent that identity, strength, quality or purity of drugwill be affected”.

for packing of ointments the following can be used

1. ALUMINIUM TUBES

They should be used with special internal epoxy coatings

2. PLASTIC TUBES

a. LOW DENSITY POLYETHYLENE(LDPE)

soft & flexible & offer good moisture protection

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b. HIGH DENSITY POLYETHYLENE(HDPE)

harder but offer high moisture protection

c. POLYPROPYLENE CONTAINERS

High thermal resistance

d. POLYETHYLENE TEREPHTHALATE(PEP)

Transparent, provide superior chemical compatibility

ointments, creams & gels are most frequently packed in 5, 15, &30g tubes. Ophthalmic ointments should packed in small aluminium orcollapsible plastic tubes holding 3.5g of ointment

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STORAGE OF SEMISOLIDSSemisolids should stable under various real world storage conditions asper ICH guidelines. They should be stored at temperatures notexceeding 25 unless otherwise authorised. They should not be allowedto freeze & must be stored in a well closed container or if thepreparation contains water or other volatile ingredients, store in an airtight container. If the preparation is sterile, store in a sterile, air tight,tamper proof container.

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REFERENCES

www.pharmtech.com

www.sphinxsai.com

www.niazi-pharmaceuticalinfo.blogspot.com

www.mypharmaguide.com

Novel semisolids by L.M. College of pharmacy

www.Wikipedia.com

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Thank youPriyanka Modugu

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