DERMATOLOGICALS

Presented by: Rikesh Lal Shrestha

Kathmandu University M.Pharm, 2nd sem.

2015-2017

CONTENTS

• INTRODUCTION• FORMULATION OF SEMISOLID DOSAGE FORM• METHODS OF PREPARATION• EVALUATION PARAMETERS• RECENT ADVANCES IN SEMISOLIDS• NOVEL ADVANCES IN SEMISOLID APPLICATION• RECOMMENDATION AND CONCLUSION• REFERENCE

INTRODUCTION• Dermatologicals are usually semi-solid dosage forms

having a semi-solid consistency which when applied to the skin performs therapeutic, protective or cosmetic function.

• Semi solids comprises the group of products which when applied to the skin or mucous membrane tend to alleviate or treat a pathological condition or offer protection against a harmful environment.

• They have a property to cling to the skin.• The addition is due to the plastic rheological behavior.• They are intended for localized drug delivery. [1]

Ideal properties of semi solids• Physical properties

Smooth texture Non dehydrating Non gritty and non greasy Elegant in appearance [6]

• Physiological properties Non irritating Do not alter membrane or physical properties Miscible with skin secretion. [6]

• Application properties Easily applicable with efficient drug release High aqueous wash ability. [6]

Advantage of semi-solid dosage form:

• It can be used externally.• Probability of side effect can

be reduced.• Can be use for Local action.• First pass gut and hepatic

metabolism is avoided.• Patient compliance is

increased, the drug termination is problematic cases is facilitated as compared with other routes of drug administration. [2]

Disadvantages of semi-solid dosage form:

• There is no dosage accuracy in this type of dosage form

• The base which is used in the semi-solid dosage form can be easily oxidized.

• Possibility of allergic reactions.• Can be used only for drugs

which require very small plasma concentration for action.

• Enzyme in epidermis may denature the drugs.

• Drugs of larger particle size not easy to absorb through the skin. [2]

TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS• Ointments: They are semisolid preparations for external

application to skin or mucous membranes. Function as skin protective and emollients. They are greases with the permissible addition of up to 25% of powder by weight. [4]

• Creams: They are semisolid dosages forms that contain one or more drug substances dissolved or dispersed in a suitable base, usually an oil in-water emulsion or aqueous microcrystalline dispersion of long-chain fatty acids or alcohols that are water-washable and are cosmetically and aesthetically acceptable. [4]

• Gels: They 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. [4]

• Pastes: They are greases containing more than 25% powder by weight are semisolid dosage forms that contain one or more drug substances incorporated in a base with large proportions of finely dispersed solids. They are intended for external application to skin, but very thick and stiff. [4]

HUMAN SKIN• The human skin consists of three

major layers :a) Epidermisb) Dermisc) Subcutaneous tissues [1]

ROUTE OF PENETRATIONWhen a drug is applied topically, the drug diffuses out of its vehicle on to the surface tissue of the skin. There are three potential portals of entry:

1) Through the follicular region,2) Through the sweat ducts and 3) Through the unbroken stratum corneum

between these appendages. [1]

Fig1: Cross section of human skin Fig2: Diagrammatic representation showing routes of penetration. [4]

MECHANISM OF SEMISOLIDS DRUG PENETRATION

Fig3: Absorption of semisolid dosage form through skin

FACTORS AFFECTING SKIN PENETRATIONa) Physicochemical factor: Hydration of stratum corneum is one of the most important

factors that increase the penetration of the drug substance that penetrate skin. Hydration can occur either by water diffusing from underlying epidermal layers or from perspiration. Eg: during steroid therapy, the occlusive plastic film increase water concentration in the stratum corneum and enhance the penetration of steroid. [1]

b) Temperature: The occlusive vehicles of semi solid drug product increase the skin temperature by few degrees but increase skin permeability is small compare to the effect of hydration. [1]

c) pH: According to partition hypothesis, only unionized molecule pass easily across lipid membranes. But ionized molecules do penetrate stratum corneum to some extent as they have great aqueous solubility than neutral species. [1]

d) Molecular size: There is little correlation between molecular size and penetration rate. Drug having small molecular size penetrate skin more rapidly than large molecular size drug. [1]

Raw Materials• During selection of raw materials, that materials whose chemical and

physical incompatibilities affect therapeutic efficacy of drug must be avoided.

• Drug solubility in various materials, indicate the type of base most suitable for the stability of the drug and for its absorption.

• Raw materials compatibility with container is very importance, and also stability studies of the finished product must be performed. [1]

Fig4: The basic raw materials used in the development of various semisolid dosage forms. [4]

FORMULATION OF SEMISOLID DOSAGE FORM• The formulation of semi solid dosage form

includes:BasesAntimicrobial PreservativeHumectantsAntioxidantsEmulsifierGelling agentPermeation enhancerBufferPerfume

BASESThere are four types of bases that are used to formulate pharmaceutical semi solids preparation:

a) Hydrocarbon bases/ oleaginous bases: These bases are anhydrous, non washable and does not absorb water. They should not be applied to infected skin. They are used as protectant, emollients, and vehicles for hydrolysable drugs. Example: White Petrolatum, White Ointment. [5]

b) Absorption bases: These bases are anhydrous substances which have the property of absorbing (emulsifying) considerable quantity of water but still retaining their ointment –like consistency. They are two types: (i) Non-emulsified bases: it absorbs water and aqueous solution producing w/o emulsion. Eg: Wool fat (ii) Water in oil emulsion: it is capable of absorbing more water and have the properties of non-emulsified bases. Eg: hydrous wool fat (Lanolin),Nieva [5]

c) Water removal bases: They are oil-in-water emulsions and are referred to as cream. The vanishing cream fall into this category. The vanishing cream are termed so because upon application and rubbing into the skin, there is little or no visible evidence of their former presence. Due to presence of oil-in-water emulsifier the cream get vanish from the skin. [1]

d) Water soluble bases: They are prepared from mixture of high and low molecular weight polyethylene glycols. Suitable combination of high and low polyethylene glycols yields products having an ointment like consistency, which soften and melts when applied to skin. They are also known as greaseless ointment bases. No water is required for their preparation. They are water soluble because of presence of many polar groups and ether linkages.[1]

• ANTIMICROBIAL PRESERVATIVES: Some base, although, resist microbial attack but because of their high water content, it require an antimicrobial preservative. Example: Methyl hydroxyl benzoate, Propyl- hydroxybenzoate, Chlorocresol, Benzoic acid. [5]

• ANTIOXIDANTS: They are added to semisolid preparation whenever oxidative deterioration is anticipated. Its selection depends upon the toxicity, irritancy and stability of product. Example: Butylated hydroxy anisole, Butylated hydroxy toluene. [6]

• HUMECTANTS: They are used in semisolids to increase solubility, skin penetration of active ingredients and to elevate the hydration of the skin. Example: Poly Ethylene Glycol, Glycerol or Sorbitol is added as humectants. [6]

• GELLING AGENT: They forms a gel dissolves in a liquid phase as a colloid mixture that forms a weakly cohesive internal structure. Example: Sodium alginate. [6]

• EMULSIFIER: Ideal emulsifier must reduce surface tension for proper emulsification and have ability to increase the viscosity at low concentration. [6]

• BUFFERS: They are added to make semisolids preparation compatible with skin, for drug stability and drug solubility. Example: Sodium acetate. [6]

• PRMEATION ENHANCERS: Penetration enhancer works by reversibly disordering the lamellar packing of stratum corneum, increasing the thermodynamic activity of the drug and increasing the amount of drug in solubilized form at the skin surface. Example: Limonene, Geraniol [6]

• FRAGRANCES: They are added for the patient compliance. Examples of widely use fragrances are Lavender oil, Rose oil, Lemon oil, Almond oil [6]

METHODS OF PREPARATION• There are four methods of preparation of semi solids dosage form.

1) TRITURATION METHOD:- It is commonly used method when base contains soft fats and oils, or medicaments in insoluble or liquid. It is carried out in mortar and pestle. [5,6]

2) FUSION METHOD:- On small scale fusion method is carried out in a porcelain dish placed over water bath. Here the ingredient of high melting point is melted then remaining ingredient of bases are added in the decreasing order of their melting points and melted with constant stirring. [5,6]

3) CHEMICAL REACTIONS:-In chemical reaction method a product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of such method is Iodine ointment. [5,6]

4) Emulsification Method:

The four steps involve in this method are:a) Preparation of oil and aqueous phase: The components of the oil or fat mixture are placed

into a stainless steel steam-jacketed kettle and melted. The kettle is heated to a temperature of oil phase to prevent its components from congealing. The components of the aqueous phase are dissolved in the purified water and also aqueous soluble drug can be added to it.

[5,6]

b) Mixing of the Phases: The phases are usually mixed at the temperature of 70-720C, because at this temperature intimate mixing of the liquid phase can occurs. The phase mixing temperature can be lowered a few degree if the melting point of the fat phase is low enough to prevent the premature crystallization. The phase can be mixed by three ways: (i) Simultaneous blending of the phase (ii) Addition of discontinuous phase to continuous phase (iii) Addition of continuous phase to discontinuous phase. [5,6]

c) Cooling the emulsion: The rate of cooling is generally slow to allow adequate mixing while emulsion is still liquid. The temperature of cooling medium in kettle jacket should be decrease at a rate consistent with the mixing of the emulsion to prevent formation of the congealed masses of ointment or cream. The perfume must be added at a 43-450C temperature. [5,6]

d) Homogenization: Those semi solids preparations that need further treatment are then transfer or pumped to homogenizer, the selection of which is governed by the degree and the rate of shear stress required. The choice includes a low-shear pump, a roller mill, a colloid mill and a valve type homogenizer. Uniform dispersion of an insoluble drug in a semi solid, as well as reduction of the size of the fatty aggregates can be achieved by the passage of the warm ointment or cream through a homogenizer or mill. [5,6]

EVALUATION PARAMETERS OF SEMI SOLID DOSAGES FORM

a) Evaluation of gel [7]

– Drug content– Measurement of pH– Viscosity– Spreadability– Extrudability

b) Evaluation of ointments [7]

– Penetration– Irritant effect

d) Evaluation of paste [7]

– Abrasiveness– Particle size– Cleansing property– Consistency

e) Evaluation of cream [7]

– Sensitivity– Biological testing– Phase separation– Globule size– Rheological properties

RECENT ADVANCES IN SEMISOLIDS• RECTAL OINTMENT• CREAMS CONTAINING MICROSPHERES• LAMELLAR FACED CREAMS • CREAM CONTAINING LIPID NANOPARTICLES• ORGANOGEL OF SORBITAN MONOSEARATE• ORGANOGELATION OF LECITHIN• AMPHIPHILIC GEL• BIOADHESIVE GEL• THERMOSENSITIVE SOL-GEL REVERSIBLE HYDROGEL• COMPLEXATION GEL

1) RECTAL OINTMENT: It is used for the symptomatic relief against inflammation associated with hemorrhoids, anal fissure and fistulas. Rectal ointment should be applied several times in a day according to the severity of the condition. For intrarectal use, special applicator are also available. [2]

2) CREAMS CONTAINING MICROSPHERES: Albumin microsphere containing vitamin A can be administered by using creams topically. 222 ± 25 μm size of microsphere of vitamin A were produced by emulsion method. The In-vivo study revealed that these microspheres were able to remain on skin for long period of time, and prolong the release of vitamin A [2]

3) LAMELLAR FACED CREAMS: They are liquid paraffin in water emulsion prepared from cetrimide / fatty alcohol like mixed emulsifiers and ternary system formed by dispersing the mixed emulsifier in require quantity of water. The cationic emulsifying wax showed phenomenal swelling in water and this swelling was due to electrostatic repulsion which can be suppressed by addition of salt and can be reduced by changing surfactant counter ion. [2]

CREAM CONTAINING LIPID NANOPARTICLES: • Occlusion of cream is important criteria since it increases

the penetration of topical drugs. This can be achieved by using oils and semisolid paraffin in large quantities.

• The development of a water-in-oil cream containing small particles of solid paraffin was studied.

• Solid paraffin nanoparticles were incorporated in the aqueous phase of a water-in-oil cream wherein the aqueous phase was divided into small droplets.

• Here the oil phase served as a lubricant for nanoparticles.• Hence cream containing nanoparticles have a high degree

of occlusivity and also prevent a rough feel during application. [2]

Oraganogel of Sorbitan monostearate: • Sorbitan monostearate is a hydrophobic nonionic surfactant, gels a number of organic solvents such as

hexadecane, isopropyl myristate, and a range of vegetable oils.• Gelation is achieved by dissolving/dispersing the organogelator in hot solvent to produce an organic

solution/dispersion, which, on cooling sets to the gel state. • Cooling causes a decrease in the solvent-gelator affinities, such that the surfactant molecules self-assemble into

toroidal inverse vesicles. Further cooling results in the conversion of the toroids into rod-shaped tubules. • Once formed, the tubules associate with others, and a three-dimensional network is formed which immobilizes

the solvent. An organogel is thus formed. • Sorbitan monostearatre organogels has ability to solubilise poorly water soluble drugs so it is use as delivery

vehicles for drugs. [2]

Organogelation of Lecithin: • Initially, the lecithin molecules are randomly dispersed in the organic medium. • With the addition of small amount of water, the lecithin molecules will assemble in spherical reverse micellar

form. • Further addition of water makes the cylindrical micellar aggregate. The water molecules bind to hydrophilic

head of the lecithin molecules. • A further increase in a small amount of water results in the formation of long and flexible tubular micellar

structures . • Thousands of such tubular micro-structures overlap and entangle with each other to form a three-dimensional

gel network. Then organic liquids get entrapped in the spaces between the entangled reverse micelles. [8]

Fig7: Process of Organogelation[8]

Amphiphilic gels:

• Amphiphilic gels can prepared by mixing the solid gelator like sorbitan monostearate or sorbitan monopalmitate and the liquid phase like liquid sorbitan esters or polysorbate and heating them at 60°C to form a clear isotropic sol phase, and cooling the sol phase to form an opaque semisolid at room temperature.

• Amphiphilic gel microstructures consisted mainly of clusters of gelator molecules tubules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase.

• At temperatures near the skin surface temperature, the gels softened considerably, this would allow topical application. [9]

Fig8: Amphiphilic gel structure [9]

BIOADHESIVE GELS: • Chitosan bioadhesive gel was formulated for nasal delivery of insulin. • The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium

molecular weight of chitosan, and lecithin or EDTA. Drug release was studied by a membraneless diffusion method and bioadhesion by a modified tensiometry test.

• Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin.

• The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction the glucose level by as much as 46% of the intravenous route. [2]

Thermosensitive sol-gel reversible hydrogel:

• They are the aqueous polymeric solutions which undergo reversible sol to gel transformation under the influence of environmental conditions like temperature and pH which results in in-situ hydrogel formation. [9]

• Advantages : a) It is easy to mix pharmaceutical solution rather than semisolids b) Biocompatibility with biological systems c) Convenient to administerd) The pharmaceutical and biomedical uses of such sol-gel transition

include solubilization of low molecular-weight hydrophobic drugs

e) Release can be in a controlled fashion. [9]

Complexation gels: - • The goal of oral insulin delivery devices is to protect the sensitive

drug from proteolytic degradation in the stomach and upper portion of the small intestine.

• In this work, pH-responsive hydrogels are used as oral delivery vehicles for insulin.

• Insulin was loaded into polymeric microspheres and administered orally to healthy and diabetic Wistar rats.

• In the acidic environment of the stomach, the gels were unswollen due to the formation of intermolecular polymer complexes. The insulin remained in the gel and was protected from proteolytic degradation.

• In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid gel swelling and insulin release. [7]

IDEAL PROPERTIES OF NOVEL SEMISOLIDS:

a) Novel ointment bases: i) Should absorb more water and enhance permeation. ii) When applied over skin,an oleaginous ointment film should formed which prevents moisture evaporation from the skin. iii) Should not irritate skin. Substances (e.g., hydrocarbon bases) conform an occlusive barrier on the skin that prevents.

b) Novel semisolids are safe even when applied to inflamed skin. c) They should be odorless, easy to handle, stable and compatible with large range

of drugs and should be safed) Use of Novel semisolids in pediatric, geriatrics and pregnant women should be

safe without causing any allergic reaction. e) Novel semisolids should able to extend the release pattern in a controlled

manner. f) Novel semisolid should allow its use in different routes of administration with

safe, odorless, easy to handle and compatible with biological membrane. [9]

NOVEL ADVANCES IN SEMISOLID APPLICATIONS• Nasal route• Nasal gels are semisolid preparations in a water soluble or water miscible vehicle

which can be use for local or systemic effect where as Nasal ointments are prepared from either water miscible/soluble or oleaginous bases. [9]

• Uses: An example of drug that shows effectiveness upon administration as a nasal gel, as compared to an oral tablet, is vitamin B12, where clinical studies showed a 2.5 fold increase in measurable vitamin B12 in the blood at 48 hours after administration. [9]

• Ophthalmic:In ocular drug delivery many physiological constraints prevent the successful drug delivery to eye. Drug loss occur due to:

1) less capacity of cual-de-sac2)dilution of drug due to lachrymal secretion3) Nasolachrymal drainage

So formulation administrated by increasing the viscosity of dosage form.Uses : Wide range of eye ointment are available for effective treatment of eye infection. E.g. acyclovir eye ointment chloramphenicol ophthalmic ointment. [9]

Rectal routeIt includes ointment, cream,gel for application to perianal area.

Advantages:• Large surface area• By pass First pass hepatic metabolism• Prolong residence time• Permeability to large mol. Weight drugs such as peptide and proteins.• Insulin gel administrated deep rectally [9]

SKIN: -Delivery of drugs to the skin is an effective and targeted therapy for local dermatological disorders.

Advantage :(1) Provides a largest surface area(2) It avoids first-pass effects, gastrointestinal irritation,(3) And metabolic degradation associated with oral administration. [9]

PACKAGING OF NOVEL SEMISOLIDS• Containers, closures and other component must not

be reactive with the semi solid preparation.• All drug product containers and closures must be

approved by stability testing of product in the final container in which it is marketed.

• This includes stability testing of filled container at room temperature about 200C as well as under accelerated stability testing condition around 40 - 500C. [9]

RECOMMENDATION • Use of semi solid dosage form in nasal and

transdermal delivery must be explored and research must be continued.

• If topically applied semisolid could provide maximum bioavailability then it would be the most efficient route of drug delivery as it bypasses first pass metabolism and also possess patient compliance .

CONCLUSION

• Hence we can conclude that great opportunities for the development of semisolid dosage forms exist because of the diverse class of drugs that are proposed for topical delivery.

References1) Lachman L, Lieberman H. A, Kanig J. L., Theory and Practice of Industrial Pharmacy. 4th Indian

Edition. 1991, Verghese Publishing House. 534- 563.2) Patel Pinkesh, et al , “Recent Advances in Novel Semisolid Dosage Forms: An Overview”, Journal

of Biomedical and Pharmaceutical Research 2 (1) 2013, 09-14 Page9 ISSN: 2279 - 0594 ,”3) Debjit Bhowmik1* , Harish Gopinath1 ,“Recent Advances In Novel Topical Drug Delivery

System”, ISSN: 2277- 7695 CODEN Code: PIHNBQ ZDB-Number: 2663038-2 IC Journal No: 7725 Vol. 1 No. 9 2012

4) Sonje A.,Thube R.,Parmar V.,Kumari G.,Deshpande P, “A review on penetration enhancers for semi solids”, Asian journal of pharmaceutical research and development, vol 1(5),94-107,sept-oct 2013.

5) www.authorstream.com/Presentation/6928373561-1947670-semisolid-dosage-forms6) www.slideshare.net/docmano15/semi-solid-dosage-forms7) Aditya Bora, Sambhaji Deshmukh , “Recent advances in semisolid dosage form”, International

Journal of Pharmaceutical Sciences And Research”Inclusion in Web of Science (Thomson Reuters) – ESCI Projected Impact Factor (2015): 1.11

8) Sushil Rauta,n , Santosh Singh Bhadoriyaa et al,” Lecithin organogel: A unique micellar system for the delivery of bioactive agents in the treatment of skin aging”, Acta Pharmaceutica Sinica B 2012;2(1):8–15

9) Mandore Paresh; Sharma R.K.; et al, “A Review : Novel Advances in Semisolid Dosage Forms & Patented Technology in Semisolid Dosage Forms”, International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol. 3, No.1, pp 420-430, Jan-Mar 2011

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