Saturday, May 23, 2009

Semisolid Dosage Forms

Semisolid pharmaceutical systems comprise a body of products, which when applied to the skin or accessible mucous membranes tend to allevate or treat a pathological condition or offer protection against a harmful environment.
They have the property to cling to the skin or mucous membrane for a protracted period of time to exert their therapeutic effect through protection and occlusion. The adhesion is due to their plastic rheologic behavior which allows semisolid to retain their shape and cling as film until acted upon by an outside force.
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 drugs. Semisolids constitute a significant proportion of pharmaceutical dosage forms. They can be applied topically to the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining.

Fig:-1.1:Categories of pharmaceutical Dosage Forms (3)
Several novel drug-carrier systems have been examined that offer modified release of a drug or a stable environment for the incorporation of a drug.
1.1DEFINITION (4): -
Semisolid dosage forms are dermatological products of semisolid consistency and applied to skin for therapeutic or protective action or cosmetic function.
1.2 IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS (4, 5):-
1.2.1 PHYSICAL PROPERTIES: -
a)Smooth texture
b)Elegant in appearance
c)Non dehydrating
d)Non gritty
e)Non greasy and non staining
f)Non hygroscopic
1.2.2 PHYSIOLOGICAL PROPERTIES: -
g)Non irritating
h)Do not alter membrane / skin functioning
i)Miscible with skin secretion
j)Have low sensitization index
1.2.3 APPLICATION PROPERTIES: -
k)Easily applicable with efficient drug release.
l)High aqueous washability.
1.2.4 STORAGE PROPERTIES: -
Stable under various real world storage conditions as per ICH guidelines. Storage of semisolids should be at temperatures not exceeding 25° unless otherwise authorized. They should not be allowed to freeze and must be stored in a well-closed container or, if the preparation contains water or other volatile ingredients, store in an air-tight container. The containers are preferably collapsible metal tubes from which the preparation may be readily extruded. If the preparation is sterile, store in a sterile, airtight, tamper-proof container.
Climatic zones
Definition

Storage/test conditions

Example
I
Temp. climate
21°C + 2°C and 45% RH + 5% RH
Northern Europe, Canada
II
Mediterranean & subtropical climate
25°C + 2 °C and
60% RH + 5% RH
Southern Europe, Japan, US
III
Hot dry climate
30°C + 2°C and 35% RH + 5% RH
Egypt, Sudan
IV
Hot, humid climate
30°C + 2°C and 75% RH + 5% RH
Central Africa, South Pacific
RH = Relative Humidity
Table 1.1 : Definition and storage/test conditions for four climatic zones (5)
2 TYPES OF CONVENTIONAL SEMISOLID DOSAGE FORMS AND THEIR PROPERTIES:-
Semisolid includes ointments, creams, pastes, gels and many more.
2.1 OINTMENTS (2, 6):-
They are soft hydrocarbon based semisolid preparation, composed of fluid hydrocarbon meshed in a matrix of higher melting solid hydrocarbon petrolatum being a tasteless, odorless, unctuous material with a melting range. Since they are greasy nature so they stain cloths. Principle ingredients forming the system hydrocarbon and silicon oil are generally poor solvent for most drugs, seemingly setting a low limit on the drug delivery capabilities of the system.
2.2 CREAMS (1, 2, 6): -
They are viscous semisolid emulsion system with opaque appearance as contrasted with translucent ointments. Consistency and rheological character depends on weather the cream is w/o or o/w.
Properly designed O/W creams are elegant drug delivery system, pleasing in both appearance and feel post application.
O/W creams are non greasy and are rinsable.
They are good for most topical purpose and are considered particularly suited for application to oozing wounds.
2.3 PASTES (2, 6):-
Pastes are basically ointments into which a high percentage of insoluble solid has been added. The extraordinary amount of particulate matter stiffens the system through direct interactions of the dispersed particulates and by adsorbing the liquid hydrocarbon fraction the vehicle on the particle surface.
Pastes are usually prepared by incorporating solids directly into a congealed system by levigation with a portion of the base to form a paste like mass. The remainders of the base are added with continue levigation until the solids are uniformly dispersed in the vehicle.
·Paste are less penetrating and less macerating and less heating than ointment.
·Paste make particularly good protective barrier when placed on the skin for, in addition to forming an unbroken film, the solid they contain can absorb and thereby neutralize certain noxious chemicals before they ever reach the skin.
·Like ointments, paste forms an unbroken relatively water – impermeable film unlike ointments the film is opaque and therefore, an effective sun block accordingly. Skiers apply paste around the nose and lips to gain a dual protection.
·Pastes are less greasy because of the absorption of the fluid hydrocarbon fraction to the particulates.
·There are two types of paste, a) Fatty pastes (eg: - zon paste) and
b) Non greasy pastes (eg: - bassorin paste is also named as tragacanth jellies since hydrophilic component of tragacanth gels in water).
2.4 GELS (JELLIES) (1, 2, 6 , 7) :-
Gels are semisolid system in which a liquid phase is constrained within a 3-D polymeric matrix (consisting of natural or synthetic gum) having a high degree of physical or chemical cross-linking.
Gels are aqueous colloidal suspensions of the hydrated forms of insoluble medicament.
Gels are richer in liquid than magma
Jellies are transparent or translucent non-greasy semisolid gels.
Some are as transparent as water itself, an aesthetically pleasing state, other are turbid, as the polymer is present in colloidal aggregates that disperse light.
They are used for medication, lubrication and some miscellaneous applications like carrier for spermicidal agents to be used intra vaginally with diaphragms as an adjunctive means of contraception.
2.5 POULTICES (7):-
It is soft, viscous, pasty preparation for external use. They are applied to skin while they are hot. Poultice must retain heat for a considerable time because they are intended to supply warmth to inflamed parts of body.
E.g. Kaolin poultice (B.P.C.)
2.6 PLASTERS (4):-
Plasters are solid or semisolid masses adhere to the skin when spread upon cotton felt line or muslin as a backing material and they are mainly used to,
·Afford protection and mechanical support.
·Furnish an occlusive and macerating action.
·Bring medication into close contact with the surface of the skin.
2.7 RIGID FOAMS (1):-
Foams are system in which air or some other gas is emulsified in liquid phase to the point of stiffening.
E.g. shaving creams, whipped creams, aerosolized shaving creams.
3. THEORY OF SEMISOLID DOSAGE FORMS: -
3.1 HYDROPHILIC PROPERTIES (8):-
The water absorbing capacity of oleaginous and water-in-oil bases may be expressed in terms of the water number, defined in 1935 by Casparis and Meyer as the maximum quantity of water that is held (partly emulsified) by 100g of a base at 20o C. The test consists of adding increments of water to the melted base and triturating until the mixture has cooled. When no more water is absorbed, the product is placed in a refrigerator for several hours, removed, and allowed to come to room temperature. The material is then rubbed on slab until water no larger exudes, and finally, the amount of water remaining in the base is determined.
3.2 RHEOLOGICAL PROPERTIES (8, 9):-
Different semisolid dosage forms exhibit different rheological properties. Semisolids do not flow at low shear stresses but undergo reversible deformation like elastic solids. When a characteristic shear stress, called the yield value or yield stress, is exceeded, they flow like liquids. Yield stresses usually are caused by structural networks extending throughout an entire system. To break such a network requires stress produce no flow but only elastic deformation. When the yield stress is exceeded, the network is partly ruptured and flow occurs.
Gels - Gels or jellies are characterized by a comparatively high degree of elasticity. They undergo rather large elastic deformation at shear stresses below the yield value, from which they recover their shape when the stresses are removed. Recoverable deformations of 10 to 30% are not unusual, especially for polymer gels. Clay gels are less elastic and more like pastes.
Pastes - Pastes have little elasticity. They cannot recover their shape except from very small deformations. At stresses above their yield values, pastes turns into free-flowing liquids. This type of behavior is called plasticity. Brownian motion builds up the networks in gels and pastes and restores them when they have been ruptured by stress higher then yield stress. Examples of plastic materials are ointments and pastes, creams, butter and margarine, dough, putties and modeling clay.

Fig:-3.1: Different rheological properties of petrolatum base of different concentration (8)
Semisolids with high yield values are described as “hard”. When their plastic viscosity is high, they are described as “stiff”. Best instrument for determining the rheologic properties of pharmaceutical semisolid is some form of a rotational viscometer. The cone-plate viscometer is particularly well adapted for the analysis of semisolid emulsions and suspensions. The stormer viscometer, consisting of a stationary cup and rotating bob, is also satisfactory for semisolids.
Consistency curve for the emulsifiable bases, hydrophilic petrolatum and hydrophilic petrolatum in which water has been incorporated, are shown in fig.3.1. It will be observed that the addition of water to hydrophilic petrolatum has lowered the yield-point. The plastic viscosity (reciprocal to the slop of the downcurve) and the thixotropy (area of the hysteresis loop) are increased by the addition of water to hydrophilic petrolatum.
Fig.3.2 shows the change in plastic viscosity and thixotropy of petrolatum and plastibase as a function of temperature. The modified stromer viscometer was used to obtain the curves. As observed in figure both bases show about the same temperature coefficient of plastic viscosity. These results account for the fact that the bases have about the same degree of ‘softness’ when rubbed between the fingers.
and plastibase as function of temperature" height=288 alt="Plastic viscosity and thixotropic behaviour of petrolatum and plastibase as function of temperature" src="http://www.pharmainfo.net/files/images/stories/article_images/Plastic_viscosity_thixotropic_behaviour%20.jpg" width=336>
Fig:-3.2 : Plastic viscosity and thixotropic behaviour of petrolatum and plastibase as function of temperature (8)
Rigidity and viscosity are two separate parameters used to characterize the mechanical properties of gels. Ling studied the effect of temperature on rigidity and viscosity of gelatin. He used a rigidity index, f, which is defined as the force required depressing the gelatin surface fixed distance. To measure rigidity, a sample of gelatin solution or gel mass is subjected to penetrative compression by a flat-ended cylindrical plunger that operates at a constant speed. In this method, the stain rate (rate of deformation of gel) is constant and independent of stress (force applied). Long found that thermal degradation with respect to rigidity followed second-order kinetics,
- df / dt = kf f2
1/f – 1/fo = kf t
Where f is the rigidity index of the gelatin solution or gelatin gel at time t, fo is the rigidity index at time zero, kf is the rate constant (g-1 hr-1), and t is the heating time in hours, where g stands for gram. The quantities fo and kf can be computed forms the intercept and the slope of equation at a given temperature.

Fig:-3.3 : Thixotropic behaviour of petrolatum and plastibase as a function of temperature (8)
The effect of temperature on the rate constant kf can be expressed using the Arrhenious equation,
Kf = Ae –Ea/RT
Thus, a plot of ln Kf against the Arrhenious constant A and the energy of activation Ea.
Rheological changes: -
Homogenization frequently increase the consistency of semisolid emulsion because it increase the number of emulsified particle. Homogenization can also have the opposite effect that of decreasing the viscosity of the product owning to electrolyte effect. Some creams are sensitive to agitation and stress. The continuous rotation of an auger in the hopper of the filling machine may cause cream to liquefy. Such creams may be made more resistance to agitation by a formula change.
3.3 ROUTE OF ABSORPTION (2, 10): -

Fig:-3.4: Route of absorption (10)
Semisolid dosage forms for dermatological drug therapy are intended to produce desired therapeutic 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 (physicochemical properties), the carrier base and skin condition.
The skin is made up of several layers including stratum corneum, viable epidermis and dermis, and it contains appendages that include sweat glands, sebaceous glands, and hair follicles. The stratum corneum is the outermost desquamating ‘horny’ layer of skin, comprising about 15-20 rows of flat, partially desiccated, dead, keratinized epidermal cells
Both topical and transdermal drug products are intended for external use. However, topical dermatologic products are intended for localized action on one or more layers of the skin (e.g. sunscreens, keratolytic agents, local anesthetics, antiseptics and anti-inflammatory agents). Although some medication from these topical products may unintentionally reach systemic circulation, it is usually in sub-therapeutic concentrations, and does not produce effects of any major concern except possibly in special situations, such as the pregnant or nursing patient.
When a drug system 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: through the follicular region, through the sweat ducts, or through the unbroken stratum corneum between these appendages.
Absorption by the transdermal route, penetration is fairly rapid, although slower than intestinal tract absorption, and is almost always accompanied by some degree of pilosebaceous penetration as well.
Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug transport across the stratum corneum follows Fick’s Law of Diffusion,
dA = D.∆C.K
dt h
Where:- i) dA/dt is the steady-state flux across stratum corneum
ii) D is the diffusion coefficient or diffusivity of drug molecules
iii) ∆C is the drug concentration gradient across the stratum corneum
iv) K is the partition coefficient of the drug between skin and formulation medium, and
v) h is the thickness of the stratum corneum
In particular, the transient diffusion that occurs shortly after the application of a substance to the surface of the skin is shown to be potentially far greater through the appendages than through the matrix of stratum corneum. After the steady state has been established, the dominant diffusion mode is probably no longer intra appendageal, but occurs through the matrix of stratum corneum. The recognition of transient diffusion, occurring primarily via follicles and ducts, and steady state diffusion, occurring primarily through the intact stratum corneum, results in a considerably more self consistent and orderly treatment of the process of percutaneous absorption.
The concentration gradient ends in the dermal layer at the beginning of the circulation. The systemic circulation acts as a reservoir or “sinks” for the drug. Once in the general circulation, the drug is diluted and distributed rapidly with little systemic build up.
Diffusion through the horny layer is a passive process. The passive process is affected only by the substance being absorbed, by the medium in which the substance is dispersed and by ambient conditions. On the other hand, percutaneous absorption is the more complicated process, of which epidermal diffusion is the first phase and clearance from the dermis the second which depends on effective blood flow, interstitial fluid moment, lymphatic and perhaps other factors that combine with dermal constituents.
Transport of lipophilic drug molecules is facilitated by their dissolution into intercellular lipids around the cells of the stratum corneum. Absorption of hydrophilic molecules into skin can occur through pores or openings of the hair follicles and sebaceous glands, but the relative surface area of these openings is barely 1% of the total skin surface. This small surface area limits the amount of drug absorption.
3.4 FACTORS AFFECTING SKIN PENETRATION (2): -
The factors that influence skin penetration are essentially the same as those for gastro intestinal absorption, with the rate of diffusion depending primarily on the physicochemical property of drug and only secondarily on the vehicle, pH, and concentration.
The principle physicochemical factor in skin penetration is the hydration state of stratum corneum, which affects the rate of passage of all substances that penetrate the skin. The clinical importance of hydration can be found in the use of occlusive plastic film in steroid therapy. Here, the prevention of water loss from the stratum corneum and the sub- sequent increased water concentration in this skin layer apparently enhances the penetration of the steroid. The temperature of skin and the concentration of the drug play significant roles, but they are secondary to that of hydration.
The solubility of a drug determines the concentration presented to the absorption site, the water or lipid partition coefficient influences the rate of transport. An inverse relationship appears to exist between the absorption rate and the molecular weight. Small molecules penetrate more rapidly than large molecules, but within a narrow range of molecular size, there is little correlation between the size and the penetration rate.
4. FORMULATION OF SEMISOLID DOSAGE FORMS (7):-
Inert pharmaceutical ingredients are used in combination with drugs to formulate the product. However many times topical bases are used for therapy e.g. Cold cream
4.1 INGREDIENTS USED IN PREPARATION OF SEMISOLIDS: -
Ingredients used for formulating semisolids include API, Bases, Antimicrobial preservative, Chelating agents, Humectants, fragrances.
4.1.1 ACTIVE PHARMACEUTICAL INGREDIENTS (2, 7, 11) : -
Disease treated
API
Keratolytic
Salicylic acid
Acne
Sulphur, Resorcinol
Antipruritic
Benzocaine, Menthol, Camphor
Emollient
Lanolin
Anti-inflammatory
Corticosteroid
Antifungal
Benzoic acid, Salicylic acid
Table 4.1 : Medicaments prescribed for semisolids (7)
4.1.2 BASES (7, 11, 12): -
A large number of drugs for external use are presented as semi-solid formulations e.g. ointments, suppositories, creams and pastes. While ointments are considered as semi-solids, suppositories are regarded as molded solid dosage forms. Ointment and suppository bases do not merely act as the carriers of the medicaments, but they also control the extent of absorption of medicaments incorporated in them.
An ointment base should be compatible with skin, stable, smooth and pliable, non-irritating, non-sensitizing, inert, capable of absorbing water or other liquid preparations, and of releasing the incorporated medicament, readily. A base for ophthalmic ointments must be non-irritating to the eye, should permit the diffusion of the drug through the secretions batting the eye, and should retain the activity of the medicament for a reasonable period often under proper storage conditions. It should also be sterilizable conveniently.
Appropriate Selection of Ointment Base: Selection of ointment base depends on following.
1. Desired release rate of the drug substance from the ointment base.
2. Rate and extent of topical or percutaneous drug absorption.
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.
Ointment bases may be classified in several ways but the following classification based on composition is generally used which are as follow,
A) Oleaginous bases.
B) Absorption bases.
C) Emulsion bases.
D) Water soluble bases.
E) Water removable bases.
A) Oleaginous bases: - These generally consist of a combination of more than one oleaginous material such as water-insoluble hydrophobic oils and fats. Most of the early ointment bases used to be exclusively oleaginous in nature but nowadays the materials obtained from plant, animal, mineral as well as synthetic origin are employed as oleaginous ointment bases. Combinations of these materials can produce a wide range of melting points and viscosities.
B) Absorption (Emulsifiable) Bases: - These are essentially anhydrous systems composed of hydrophobic ingredients already discussed under oleaginous 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 W/O type emulsions and have capacity to absorb considerable quantities of water or aqueous solution without marked changes in consistency. Absorption bases are mostly mixtures of animal sterols with petrolatum. Combinations of cholesterol and/or other suitable lanolin fractions with white petrolatum are available under different commercial names e.g. Eucerin and Aquaphor.
C) Emulsion Bases: - According to the type of emulsion, these bases are classified as either W/O or O/W. All W/O emulsions are not water-washable as the oil is in the external phase and O/W emulsions are used in dermatological preparations and cosmetic creams. Some of the popular creams include cold creams, vanishing creams. Skin creams, emollient creams, foundation creams, hand creams etc. Fundamentally creams can be divided into cold and vanishing types.
Types of creams depending on formulation are as follow (2, 7, 12)
1) Sterol Creams: They are water in oil emulsions where emulgent is wool fat or wool alcohol. Classical example is lanolin.
2) Soap Creams: Triethanolamine Creams are neutral soaps, produces o/w emulsion with oleic acid and triethanolamine (good emulgents for liquid paraffin)
3) Anionic Emulsifying Wax Creams: These emulsifiers produce oil in water type.
4) Cationic Emulsifying Wax Creams: These emulsifiers produce water in oil type.
5) Creams Emulsified with Non-ionic Surfactants: Cream bases prepared with Self emulsifying monostearin, a sorbitan ester, a macrogol ester, a non emulsifying wax containing a macrogol ether etc.
6) Divalent Creams: Classical example is Lime creams which is of water in oil type. Emulgent in these is Oleic acid and Calcium hydroxide.
7) Vanishing Creams: They are oil in water type creams which when rubbed onto the skin and disappear with little or no trace of their former presence.
D) Water Soluble Bases: - These include both anhydrous and hydrous dermatological non-emulsion bases which are water soluble and contain no oil phase. These are generally based on either polyethylene glycols or one or more of the other hydrocolloids.
Polyethylene glycols (Carbowaxes) are water soluble, non-volatile, unctuous compounds. They do not hydrolyse or deteriorate and do not support mold growth. They have low irritancy and dermal/oral toxicities. Carbowaxes also allow easy diffusion of medicaments to the body tissues but the degree of their absorption is low. Different grade of cabowaxes are available which are designated by a number roughly representing their average molecular weights e.g.- 200, 300, 400, 600, 1000, 1540, 4000 and 6000. At room temperature, carbowaxes 200 to 400 are clear liquids whereas carbowaxes 1000 to 60000 are white, waxy solids.
A variety of water washable ointment bases with consistencies ranging from semi-solid to solid can be obtained by blending different polyethylene glycols. Polyethylene Glycol Ointment USP is a blend of Carbowaxes 4000 and 400. Medicaments containing acidic hydrogen may interact with high molecular weight polyethylene glycols forming molecular complexes.
An example of formulation containing plastibase official in BPC is Triamcinclone Dental Paste which contain an anti-inflammatory agent Triamcinclone acetonide in adhesive, sodium CMC, pectin and gelatin.
E) Water Removable Bases: - Popular example of this includes vanishing cream.
Note: - Mineral oils are added to petrolatum to lower its fusion point, However by doing so problem of phase separation on storage is seen. These separation can be prevented by the addition of small quantities of natural waxes like ozokerite, ceresine or microcrystalline wax.
Semisolid ophthalmic vehicles contain soft petrolatum, a bland absorbing base or a water soluble base.
4.1.3 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 hydroxyl benzoate, Propyl- hydroxybenzoate, Chlorocresol, Benzoic acid, Phenyl mercuric nitrate, Benzalkonium chloride,Chlorhexidine acetate, Benzyl alcohol and Mercurial.
4.1.4 ANTIOXIDANTS: -
Example of commonly used antioxidants includeButylated hydroxy anisole, Butylated hydroxy toluene.
4.1.5 CHELATING AGENTS: -
Example of commonly used chelating agents includeCitric acid, Maleic acid
4.1.6 HUMECTANTS: -
Example of commonly used humectants includesPoly Ethylene Glycol, Glycerol or Sorbitol is added as humectants.
4.1.7 FRAGRANCES:-
Examples of widely use fragrances are Lavender oil, Rose oil, Lemon oil, Almond oil
4.1.8 IDEAL EMULSIFIER (1, 2, 6) : -
Ideal properties of emulsifier includes,
a) Must reduce surface tension for proper emulsification.
b) Prevents coalescence should quickly absorb around the dispersed phase.
c) Ability to increase the viscosity at low concentration.
d)Effective at low concentration.
Anionic
Cationic
Nonionic
Alkyl sulfates
Soaps
Dodecyl benzene sulfonate
Lactylates
Sulfosuccinates
Monoglyceride sulfonates
Phosphate ester
Silicones
Taurates
Quaternary ammonium compounds
Alkoxyalkylamines

Polyoxyethylene alkyl-aryl ethers
Polyoxyethylene fatty acid ester
Polyoxyethylene sorbitan esters
Sorbitan fatty acid esters
Glyceryl fatty acid esters
Sucrose fatty acid esters
Polyoxyethylene-polyoxypropylene block polymers
Table 4.2 :Emulsifiers
·Emulsifier HLB and its application
HLB range
Application
4 – 6
7 - 9
8 – 18
13 – 15
10 – 18
W/O emulsifier
Wetting agent
O/W emulsifier
Detergent
Solubilizers
Table 4.3 : HLB System
4.1.9 TYPES OF GELLING AGENTS (7): -
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 in gelling ability. Commonly used gelling agents are listed in table 4.3.
Material
%
Brookfield viscosity ‘CP0’
Carbomer 941resin NF
Carbomer 941resin NF
Carbomer 941resin NF
Carbomer 941resin NF
Sodium carboxymethyl cellulose
Guar gum
Methyl cellulose
Locust bean gum
Sodium alginate
0.15
0.25
0.50
1.00
1.50
1.50
2.00
2.50
2.50
2900
6300
44000
81000
5000
8040
5200
22800
10400
Table 4.4 : Gelling agents (6)
4.1.10 USE OF PERMEATION ENHANCERS IN FORMULATION OF SEMISOLID DOSAGE FORMS (13): -
Skin can act as a barrier and prevent deep penetration of drug molecules. With the introduction of various penetration enhancers, however, systemic drug delivery through the transdermal route has gained major footing.
Sr. no
Permeation enhancer
Drugs used
1.
Menthol, carvacrol, linalool
Propranolol hydrochloride
2.
Limonene
Indomethacin, ketoprofen
3.
Geraniol, nerolidol
Diclofenac sodium
4.
Oleic acid
Piroxicam
5.
Lecithin
Hydrocortisone acetate, heparin
6.
Propylene-glycol-dipelargonate
Heparin
7.
Cyclodextrins
Hydrocortisone
Table 4.5 : Penetration Enhancer used with Drugs for topical semisolids.
Penetration enhancer works by,
a) Reversibly disordering the lamellar packing of stratum corneum.
b) Increasing the thermodynamic activity of the drug,
c) Increasing the amount of drug in solubilized form at the skin surface,
In addition to the use of penetration enhancers alone, their combination with cosolvents that deliver a drug in solubilized form has led to the achievement of higher drug permeability.
Sr. no
Permeation enhancer
Cosolvent
Drugs used
1.
Isopropyl myristate
Propylene glycol
Diclofenac sodium
2.
Cineole
Ethanol
TRH analogue p-Glu-3-methyl-His-Pro amide
3.
Ethanol
Propylene glycol
Aspirin
Table 4.6 : Combination of Penetration Enhancer and Cosolvent for topical semisolids.
4.2 METHODS OF PREPARATION (7): -
There are four methods of preparation,
4.2.1 BY TRITURATION:-
When base contain soft fats and oils or medicament is and insoluble or liquid, then this method is use
4.2.2 BY FUSION:-
When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring.
4.2.3 BY CHEMICAL REACTIONS:-
In chemical method a new product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of such method is Iodine ointment.
4.2.4 BY OINTMENT MILLS:-
It is used for large scale production where triple roller mill is utilized which is faster then others.
5. RECENT ADVANCES IN SEMISOLIDS: -
A recent advance in semisolid dosage form allows modified release as well as flexibility in route of administration.
5.1 INTRODUCTION: -
Novel semisolids are non greasy since they are made up of water washable bases. Hence they cause less irritation to skin and are superior to conventional semisolid dosage form.
Novel creams now a days are provided with nanoparticles and microspheres, which has an excellent emollient effect, with better spreadability, and less staining than oleaginous ointments. However both medicated and non-medicated creams provide very good emollient effects, oleaginous ointments are preferred for dry, chapped skin in an environment of low humidity because of its occlusive properties
Number of innovation has been taken place in gels in term of modification of release pattern and also some thermoreversible gels are also introduced. Complex gels for Ora / Insulin delivery, chitosan based bioadhesive gels and TIMERx technology for controlled release, amphiphilic and non-aqueous gels are also the latest innovations in gel formulations.
Number of new bases for Gels, Ointment and Creams are developed which facilitates the delivery of above novel semisolids by various route like Nasal, Parentral or Ophthalmic route.
Care should also be used in applying any drug to inflamed skin. The integrity of inflamed skin is generally compromised, resulting in increased percutaneous migration and systemic absorption of most drugs.
5.1.1 IDEAL PROPERTIES OF NOVEL SEMISOLIDS (13): -
Ideal properties of semisolids are,
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) canform 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 safe.
d)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.
5.2 TYPES OF NOVEL SEMISOLID: -
Various types of novel semisolids used are as fallow,
5.2.1 NOVEL ADVANCES IN SEMISOLID DASAGE FORMS: -
5.2.1.1 OINTMENTS (14, 15): -
Rectal 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.
Rectal ointment should be applied several times in a day according to the severity of the condition. For intrarectal use, apply the ointment with the help of special applicator.
5.2.1.2 CREAMS: -
a) Creams containing microspheres (16): - 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 vitro and in vivo drug release of a microencapsulated and nonmicroencapsulated vitamin A cream was studied. The in vivo study in six volunteers revealed that these microspheres were able to remain on the skin for a long period of time, and as a consequence they were able to prolong the release of vitamin A
b) Lamellar faced creams (17): - 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 whish can be suppressed by addition of salt and can be reduced by changing surfactant counter ion.
c) Cream containing lipid Nanoparticles (18): -Occlusion of cream is important criteria since it increases the penetration of topical drugs. This can be achieved by using oils and fats like liquid and semisolid paraffin in large quantities. However, such formulations have the limitations of poor cosmetic properties since they have greasy feel and glossy appearance.
The development of a water-in-oil cream containing small particles of solid paraffin was studied. A high degree of occlusivity was obtained with smooth, flexible films prepared by drying aqueous dispersions of solid paraffin particles with a mean size of 200 nm (nanoparticle dispersion).However, this nanodispersion revealed a rough texture when applied. The development of a water-in-oil cream wherein the aqueous phase was divided into small droplets solved this problem. Nanoparticles were incorporated in the aqueous phase. Hence, the oil phase in which the water droplets were dispersed served as a lubricant for nanoparticles, thereby preventing a rough feel during application.
5.2.1.3 GELS: -
a)Controlled release gels (19): - Drug delivery to nasal or ocular mucosa for either local or systemic action suffers from many obstacles. Gel formulations with suitable rheological and mucoadhesive properties increase the contact time at the site of absorption. However, drug release from the gel must be sustained if benefits are to be gained from the prolonged contact time.
Gelrite gels were formed in simulated tear fluid at concentrations of polymer as low as 0.1%, and it was shown that sodium was the most important gel-promoting ion in vivo. Rheology, although it may be a questionable technique for evaluating mucoadhesive properties of polymers, showed that interactions between mucin and polymers were most likely to be seen with weak gels.
It was possible to control the release of uncharged drug substances by including surfactants that form micelles in the gel. The release depends on lipophilic interactions between the drug and the polymer and/or the micelles. Controlled-release formulations of charged drugs could be designed by mixing the drugs with oppositely charged surfactants in certain fixed ratios. In this way, vesicles in which the drug and surfactant constituted the bilayer formed spontaneously. The vesicle formation was affected by the presence of polymer, and very small vesicles that gave a slow release rate were formed when a lipophilically modified polymer was used.
The gels were also evaluated in the chamber using porcine nasal mucosa and from the results it was found that the rate of transport of drugs through the mucosa could be controlled by the rate of release from the formulation. Furthermore, the chamber can be used to evaluate the potential toxicity of formulations.
b)Organogels (20): - Sorbitan monostearate, 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 the solution/dispersion causes a decrease in the solvent-gelator affinities, such that at the gelation temperature, 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 monostearate gels are opaque, thermoreversible semisolids, and they are stable at room temperature for weeks. Such organogels are affected by the presence of additives such as the hydrophilic surfactant, polysorbate 20, which improves gel stability and alters the gel microstructure from a network of individual tubules to star-shaped "clusters" of tubules in the liquid continuous phase. Another solid monoester in the sorbitan ester family, sorbitan monopalmitate, also gels organic solvents to give opaque, thermoreversible semisolids. Like sorbitan monostearate gels, the microstructure of the palmitate gels comprises an interconnected network of rod like tubules. Unlike the stearate gels, however, the addition of small amounts of a polysorbate monoester causes a large increase in tubular length instead of the "clustering effect seen in stearate gels. The sorbitan stearate and palmitate organogels may have potential applications as delivery vehicles for drugs and antigens.
c) Extended release gels (21): - TIMERx is a controlled release technology consists of an agglomerated, hydrophilic complex that, when compressed, forms a controlled-release matrix. The matrix, consisting of xanthan and locust bean gums (two polysaccharides) combined with dextrose, surrounds a drug core. In the presence of water, interactions between the matrix components form a tight gel while the inner core remains unwetted. The drug is encapsulated in the pores of the gel, and as the matrix travels through the patient’s digestive system, the tablet swells and begins to erode. This erosion allows the drug to “back-diffuse” out through the gel-matrix at a controlled rate until the matrix erodes and a majority of the drug is released. The fundamental component controlling the rate of release lies in the properties of the gel matrix. Advantage of this system includes,
a) Predictable modified release profile like zero order or first order or initial immediate release kinetics
b) It can be manufacture on standard manufacturing equipment.
c) Cheap.
d)Amphiphilic gels (22): - 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 tubules of gelator molecules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase. The gels demonstrated thermoreversibility. Gelation temperature and viscosity increased with increasing gelator concentration, indicating a more robust gel network. At temperatures near the skin surface temperature, the gels softened considerably; this would allow topical application.This study has demonstrated the formation/preparation of stable, thermoreversible, thixtropic surfactant gels (amphiphilogels) with suitable physical properties for topical use.
e) Hydrophilic gels (23): - Hydrophilic gelsare bicoherent systems composed of the internal phase made of a polymer producing a coherent three-dimensional net-like structure, which fixes the liquid vehicle as the external phase. Intermolecular forces bind the molecules of the solvent to a polymeric net, thus decreasing the mobility of these molecules and producing a structured system with increased viscosity. The physical and chemical bonds binding the particles of the internal phase provide a relatively stable structure, which can originate by swelling of solid polymers, or by decreasing the solubility of the polymer in a solution. An important group of gels used in pharmacy are hydrophilic gels, or hydrogels, usually made of hydrophilic polymers, which under certain conditions and polymer concentration, jellify. Attention of pharmaceutical research now concentrates primarily on hydrophilic gels, as this dosage form seems to be prospective for the development of modern drugs based on systems with prolonged and controlled release of active ingredients.
f) Non aqueous gels (24): -Ethylcellulose was successfully formulated as a nonaqueous gel with propylene glycol dicaprylate/dicaprate. The novel nonaqueous gel exhibited rheological profiles corresponding to a physically cross-linked three dimensional gel network, with suitable mechanical characteristics for use as a vehicle for topical drug delivery. Molecular conformation of the solvent was found to influence the molecular interactions associated with formation of ethylcellulose gel networks.
The gel matrices exhibited prominent viscoelastic behavior, yield stress and thixotropy. Rheological and mechanical properties showed significant upward trends with increased polymeric chain length and polymer concentrations. Good linear correlations were obtained between rheological and mechanical properties. The solvent molecular conformation was found to play a role in affecting the formation of gel networks via intermolecular hydrogen bonding between ethylcellulose polymer chains.
g)Bioadhesive Gels (25): - Chitosan bioadhesive gel was formulated for nasal delivery of insulin. A nasal perfusion test was carried out to study the toxicity of four absorption enhancers like saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. 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. The optimized gel was administered nasally in diabetic rats. The serum insulin levels were analyzed by an insulin enzyme immunoassay kit and serum glucose by glucose oxidase method kits. Formulations containing 2% of low molecular weight of chitosan with EDTA had higher release percentage and dissolution efficiency (DE)2.5%, lower t50% (Time required to release 50% of the drug), mean dissolution time, and bioadhesion than gels containing 4% of medium molecular weight of chitosan with lecithin. Insulin was released by a zero-order kinetic from the gels. 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. Considering in vitro and in vivo studies, the formulated gel could be a useful preparation for controlled delivery of insulin through the nasal route.
h) Thermosensitive sol-gel reversible hydrogels (26): They are theaqueous polymeric solutions which undergo reversible sol to gel transformation under the influence of environmental conditions like temperature and pH which results in insitu hydrogel formation.
Advantages of thermosensitive sol-gel reversible hydrogels over conventional hydrogels are,
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 the such sol-gel transition include solubilization of low-molecular-weight hydrophobic drugs
e) Release can be in a controlled fashion.
f) Helps to deliver labile biomacromolecule such as proteins and genes.
g) Immobilization of cells
h) And tissue engineering
i) Complexation gels (27): - 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, the use of pH-responsive, poly (methacrylic-g-ethylene glycol) hydrogels as oral delivery vehicles for insulin were evaluated. 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. Within 2 h of administration of the insulin-containing polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. These effects lasted for up to 8 h following administration.
5.2.2 NOVEL ADVANCES IN SEMISOLID APPLICATIONS: -
5.2.2.1 NASAL (28, 29): -
Numerous drug substances can be prepared as nasal solutions or suspensions to be administered either as drops or sprays gels, jellies or ointments. Some drugs are sufficiently volatile they can be carried into the nose through an inhaler.
a) Introduction: Drug delivery to nasal mucosa for either local or systemic action faces obstacles like cilia, mucus. These routes are protected by effective mechanisms.
Nasal drug administration has been routinely used for administration of drugs for the upper respiratory tract, like adrenergic agents, and is now also being used as a viable alternative for the delivery of many systemic therapeutic agents. A number of dosage forms are common and include solutions, suspensions and gels.
Nasal gels are semisolid preparations prepared for nasal application and can be for either local or systemic use, in a water soluble or water miscible vehicle where as Nasal ointments are prepared from either water miscible/soluble or oleaginous bases.
b) Advantage, Application and uses: The advantages of nasal delivery include,
(1) Lower doses,
(2) Rapid local therapeutic effect,
(3) Rapid systemic therapeutic blood levels,
(4) rapid onset of pharmacological activity, and
(5) Few side effects.
In addition to the nasal decongestants, saline and other routine locally acting drugs, nasal administration is being investigated for the delivery of insulin, vaccines, number of poly peptides and proteins, progesterone, metoclopramide, propranolol (for migraine headaches), dihydroergotamine, desmopressin, atropine, vitamin B12 , antihistamines, anti-obesity agents, narcotic analgesics like Butorphanol tartarate (analgesic), cyanocobalamin (haematopoeitic), narfaralin acetate (treat endometriosis), nicotine (adjunct in smoking cessation) and a host of other agents.
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 six fold increase in maximum blood levels, a doubling of speed in entering the bloodstream, and a 2.5 fold increase in measurable vitamin B12 in the blood 48 hours after administration. Similar results have been reported in other studies.
c) Risk associated with nasal semisolids: The risk of patient-to-patient contamination is very high with nasally administered products; patients should be advised that a nasal product is for ONE PATIENT ONLY.
d) Formulation aspect: In addition to the active drugs, nasal preparations contain a number of excipients, including vehicles, buffers, preservatives, tonicity adjusting agents, gelling agents and possibly antioxidants. Important in the formulation process is the use of ingredients that are nonirritating and compatible with the nose as discussed within each category. In general, the same excipients used in ophthalmic formulations can also be used in nasal formulations.
It was possible to control the release of uncharged drug substances by including surfactants that form micelles in the gel. This release depended on lipophilic interactions between the drug and the polymer and/or the micelles. Controlled-release formulations of charged drugs could be designed by mixing the drugs with oppositely charged surfactants in certain ratios. In this way, vesicles in which the drug and surfactant constituted the bilayer formed spontaneously. The vesicle formation was affected by the presence of polymer, and very small vesicles that gave a slow release rate were formed when a lipophilically modified polymer was used.
The attributes of a vehicle for nasal semisolids include:
(1) pH generally in the range of 5.5-7.5, (Phosphate buffer systems are widely used and are generally compatible with most nasal medications).
(2) Mild buffer capacity,
(3) Isotonic, (The preferred agents for adjusting the tonicity of nasal solutions include sodium chloride, boric acid and dextrose. Severely hypertonic solutions should be avoided, since the nasal ciliary movement may slow or even stop. Nasal fluid is isotonic with 0.9% sodium chloride solution).
(4) Not modify the normal mucus viscosity, (A strongly hypertonic product, however, may result in a slight “drying” effect and thickening of the mucous and hypotonic product affect on the efficiency of the cilia in mucous and particulate removal).
(5) Compatible with normal ciliary motion and ionic constituents of nasal secretions,
(6) Compatible with active ingredient,
(7) Stable, (Stability is largely influenced by pH, temperature, light, oxidation and other factors. In addition to proper formulation, proper packaging is essential. Occasionally, antioxidants may be required for selected active drug ingredients).
(8) Sterile, (Nasal preparations should be sterile. Sterility is conveniently achieved through sterile filtration dry heat, steam under pressure {autoclaving} and gas sterilization {ethylene oxide}).
(9) And preserved.
e) Packing storage and labeling: Gels are packaged in either tubes or syringes for ease of administration. Generally, nasal preparations should be stored at either room or refrigerated temperatures and should not be frozen.
5.2.2.2 SKIN (7, 30, 31): -
Delivery of drugs to the skin is an effective and targeted therapy for local dermatological disorders.
a) Introduction: Topical gel formulations provide a suitable delivery system for drugs because they are less greasy and can be easily removed from the skin.
Topical dermatologic products are intended for localized action on one or more layers of the skin (e.g., sunscreens, keratolytic agents, local anesthetics, antiseptics and anti-inflammatory agents).Although some medication from these topical products may unintentionally reach systemic circulation, it is usually in sub-therapeutic concentrations, and does not produce effects of any major concern except possibly in special situations, such as the pregnant or nursing patient.
b) Advantage, application and uses: This route of drug delivery has gained popularity because,
(1) Provides a largest surface area
(2) It avoids first-pass effects, gastrointestinal irritation,
(3) And metabolic degradation associated with oral administration.
Galentic also manufactures zinc oxide ointment (5% and 25%), anti-hemorrhoid ointment, tiabendazole ointment, hydrocortisone and urea cream, fluocinole ointment, salicylic acid ointment, dexamethasone acetate and clotrimazole cream, griseofulvin ointment, white petroleum jelly (sterile or non-sterile), diclofenac diethylammonium oleum lini methyl salicylate and menthol gel (rubigel), nystatin cream / ointment, salicylic acid and precipitated sulphur ointment, fucidic acid cream, aciclovir cream and diclofenac gel. viable epidermal or dermal sites (such as local anesthetics or anti-inflammatory agents) may also occasionally include a vasoconstrictor, such as epinephrine, in the formulation to retard systemic uptake of the drugs and, thereby, prolong its local effect.
Rubigel ointment is used to reduce backache, joint pains, sprains and muscle cramp, as well as offering faster penetration of active medication thereby providing faster onset of pain relief; versept cream is used for cleansing and antisepsis of skin and mucous membranes that include wounds, burns, ulcers and abcesses. Avalon NF skin cream is a combination of Neomyci and Fluocinolone acetonide that is used for topical application.
The company also offers anti-hemorrhoid ointment for hemorrhoid patients. Betamethosone valerate ointment is used for anti-inflammatory effect; phenylephrine HCL ointment reduces bleeding and swelling, and relieves itching and discomfort by tightening the blood vessels. Lidocaine HCL local anesthetic ointment provides fast, effective and lasting pain relief.
5.2.2.3 OPHTHALMIC (28, 31-34): -
The present invention relates to novel ophthalmic pharmaceutical compositions comprising an inflammation-treating amount of a 4-aminoquinoline compound, derivative, isomers, or chemical salts, and methods for using these compositions for the treatment of ocular inflammatory conditions by topical administration directly to the eye.
a) Introduction: In ocular drug delivery, many physiological constraints prevent a successful drug delivery to the eye due to its protective mechanisms. Drug loss occur via,
(1)Less capacity of cualdy sac (up to 7.5µlit)
(2)Dilution of drug due to lachrymal secretion.
(3)Nasolachrymal drainage
So formulation is administration by increasing the viscosity of dosage form in order to achieve increase in contact time with corneal membrane. This can be achieved by use of ophthalmic semisolids
b) Ophthalmic administration: Ophthalmic semisolid compounds are useful for preventing and treating ocular inflammation by application of the compositions to the eye prior to, during and after an inflammatory disorder, especially inflammation of the outer and middle coats of the eye, such as dry eye, conjunctivitis, scleritis, keratitis, and uveitis.
c) Application and uses:Galentic supplies a wide range of eye ointments for a variety of ophthalmic infections. The product range includes aciclovir eye ointment, chloramphenicol ophthalmic ointment, gentamicin sulphate ophthalmic ointment, hydrocortisone acetate ophthalmic ointment, tetracycline hydrochloride ophthalmic eye ointment USP 1%, netracycline eye ointment (oxytetracycline eye ointment), oxytetracycline hydrochloride and hydrocortisone ophthalmic eye ointment, triosporin antibiotic eye ointment and sulphacetamide sodium ophthalmic ointment.
Uveitis is an inflammation of the uvea, the middle layer of tissue behind the white of the eye. The cause of uveitis is poorly understood, but a variety of systemic diseases are associated with it. Uveitis has been treated by various classes of compounds including steroids and nonsteroidal anti-inflammatory agents such as dexamethasone, flurometholone, prednisolone, indomethacin, aspirin, flubiprofen and diclofenac.
d) Risks of ophthalmic semisolids: Visual disturbances, including blurred vision
e) Formulation ophthalmic semisolids: The ophthalmic pharmaceutical composition of the invention includes one or more additional ophthalmic pharmaceutical compositions including buffers, surfactants, stabilizers, preservatives, ophthalmic wetting agents, and ophthalmic diluting agents. Semisolid ophthalmic vehicle contain soft petrolatum.
Absorption and water soluble bases generally are used for preparation of ophthalmic semisolids are
Mineral oil is added to petrolactum to lower its fusion point ( but its addition increases chance of separation and to avoid this Ozokerite, Ceresin, Micro crystalline wax in small quantity are added
White petrolatum (white petroleum jelly, white soft paraffin) is a white-colored, translucent, soft, unctuous mass that is inert, odorless and tasteless. It is a mixture of semisolid saturated hydrocarbons obtained from petroleum.
It is practically insoluble in ethanol, glycerin and water but is soluble in chloroform and most fixed and volatile oils. Heating above its melting range (about 70°C) for extended times should be avoided, but it can be sterilized by dry heat
f) Packaging and labeling: Package in sterile, collapsible ophthalmic ointment tubes.
For the eye. Keep out of reach of children. Use only as directed. Prevent contaminating the tip of the tube and gel; avoid contact with the eyelids or surrounding areas.
5.2.2.4 RECTAL (16, 28, 35) : -
Rectal tissues are much thicker than other gastro intestinal epithelial tissue. Bioavailability of this route depends upon pH of environment, lipid solubility of drug.
a) Introduction: rectal preparation includes Ointment, creams; gels are used for application to perianal area. Preanal area is the skin immediately surrounding anus. Substance applied rectally may be absorbs by diffusion into circulation via network of three hemorrhoid arteries (superior inferior and middle hemorrhoid artery)
b) Rectal administration: previously this route was use for bowel evacuation. But now a day’s rectal route is widely use for administration of drugs like paracetamol, aspirin, indomethacin, theophyllin, barbiturates, chlorpromazine and several other anticonvulsant agents
c) Advantage, application and uses: several advantages of using rectal semisolids are
(1)Large surface area
(2)The ability to bypass first-pass liver metabolism,
(3)Prolongs the residence time
(4)And permeability to large molecular weight drugs, such as peptides and proteins. (insulin gels administered deep rectally )
Rectal preparation are used to treat anorectal pruritis, inflammation (hydrocortisone), discomfort with hemorrhoids (hydrocortisone), pain (pramoxine hydrochloride) Astringent (for example ZnO), protectants and lubricants (coca-butter, lanolin)
d) Risks of Rectal semisolids: less frequent risk with rectal administration of drug include skin rash, dizziness, pain, headache, abdominal pain, nervousness, diarrhea, feeling unsteady or clumsy, and wheezing
e) Formulation of Rectal semisolids: Bases for preparation of anorectal ointment and creams are polyethylene glycol 300-3350, emulsion cream bases containing cetyl alcohol, cetyl ester wax, white petrolactum and mineral oil
Sr. no
Name
Company
Active ingredient
Dosage form
Use
1.
Anusol
GlaxoSmithKline
Starch
Ointment
hemorrhoids

2.
Tronolane
Ross
Pramoxine hydrochloride
Cream
hemorrhoids
Analgesic and Antipruritic
Table 5.1 : Example of rectal semisolids
Antimicrobial preservative used in formulation are methyl paraben, propyl paraben benzyl alcohol, butylated hydroxyl anisol
f) Packaging and labeling: rectal semisolids are packed in special perforated plastic tip for product to be administered into anus to treat inflammation, pain associated with hemorrhoids.
Insulin gels administered deep rectally by means of an applicator
Before application of anorectal ointment to perianal skin the affected area should be cleaned and dried

Fig 5.3 : Applicators for rectal administration (36)
Fast-response needle probes for instant readings in tissue, semisolids, and liquids. Also for very small specimens, powders and materials. Needle tip is sealed to ensure only stainless steel contacts specimen. Max. Temp. 200°C. 5 ft. lead. Smallest microprobes give fastest reading. Short probes are easier to insert and last longer.
5.2.2.5 VAGINAL(28, 37-41): -
Development of an ideal vaginal formulation with desired characteristics in terms of safety, efficacy, patient compliance, aesthetics, acceptability to regulatory authorities, and cost requires a careful and meaningful selection of the active ingredients and excipients.
a) Introduction: The vagina has been explored as a favorable site for the local and systemic delivery of drugs used for the treatment of female-specific conditions. Vaginal preparation are used as creams (like foams) and ointment gels
b) Vaginal administration: Vagina is an effective route for drug administration intended mainly for local action, but systemic effects of some drugs also can be attained.
Several formulations are available for intravaginal therapy. These include tablets, hard and soft gelatin capsules, creams, suppositories, pessaries, foams, ointments, gels, films, tampons, vaginal rings, and douches
c) Advantages, applications and uses: The major advantages of this route include
(1) Accessibility and large surface area,
(2) Good blood supply,
(3) The ability to bypass first-pass liver metabolism,
(4) Prolongs the residence time
(5) And permeability to large molecular weight drugs, such as peptides and proteins.
Among the delivery systems proposed for this route intravaginal gels, have been found to be potential vaginal drug delivery systems. The bioadhesives used in the formulation of gels play a key role in the release of the drug through the attachment to the vaginal mucosa, where the drug diffuses from the gel to the mucus.
Vaginal administration of drugs is mainly used for the treatment of local infections such as vaginitis, bacterial vaginosis, candidiasis, and other infections
Vaginally administered agents and formulations are mainly used provide protection against microbial infections, including Acquired Immune Deficiency Syndrome (AIDS) and other sexually transmitted diseases.
Microbicides, these agents and formulations are also potential vaginal contraceptives are used in treatment of vulvovaginal infection, vaginitis, anti-infective
(Clotrimazole, miconazole, clindamycin, sulfonamide), Endometrial atrophy dienesterol, progesterone are used and Contraceptive like nonoxynol-9, octoxynol are also used
d) Formulation Vaginal semisolids: Depending on the characteristics of the dosage form, excipients with different functionalities are used. All excipients present in a vaginal formulation may not be inert and therefore exhibit specific activities, which may affect the primary activity of the active molecule. Recent studies have shown that some excipients possess activities against sexually transmitted pathogens.
Sr. no
Name
Company
Active ingredient
Dosage form
Use
1.
Terazol-7
OrthoMcNeil
Terconazole
Cream
Antifungal(against Candida albicans)
2.
Premarin
Wyeth-agerst
Conjugate estrogen
Cream
vaginitis
Table 5.2 : Examples of vaginal semisolids
The ingredients normally used as excipients and possessing potent antimicrobial activities include benzalkonium chloride, sodium dodecyl sulfate/sodium lauryl sulfate, carrageenan, cellulose acetate phthalate (CAP), and undecylenic acid.
Bases uses for preparation of vaginal semisolids are of water washable type
e) Packaging and labeling: vaginal semisolids are packed in collapsible tube and Keep out of reach of children. Use only as directed
5.2.2.6 ORAL(42):-
Drug delivery through the oral route has been the most common method in the pharmaceutical applications of hydrogels. In peroral administration, hydrogels can 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 a biological fluid, hydrogels can be a useful device for releasing drugs in a controlled manner at these desired sites. Additionally, they can also adhere to certain specific regions in the oral pathway, leading to a locally increased drug concentration, and thus, enhancing the drug absorption at the release site.
Oral anesthetic gel for the temporary relief of occasional minor irritation and pain associated with minor dental procedures; minor irritation of the mouth and gums caused by dentures or orthodontic appliances like sore mouth, gum and throat; minor injury of the mouth and gums; canker sores or stomatitis.
QUEST PLUS Equine Oral Gel contains two active pharmaceutical ingredients, moxidectin and praziquantel. Kills tapeworms, Strongyles, Eencysted Cyathostomes, Pinworms, Hairworms, Ascarids, Largemouth Stomach worms and Bots.Moxidectin is safe for use in horses and ponies because it does not have the same injurious effect on the mammalian nervous system. Praziquantel increases the tapeworm’s membrane permeability to calcium and other cations causing severe contraction and paralysis of the tapeworm’s muscles. This spastic paralysis results in the inability of tapeworms to attach to the host’s intestinal wall. Detached tapeworms are either destroyed by the host’s immune defense system or passed in the feces.
5.3 PATENTED TECHNOLOGIES IN SEMISOLIDS: -
5.3.1 DELIVERY OF MONOCLONAL ANTIBODY USING SEMISOLID DOSAGE FORM (21): -
Lysostaphin was formulated into a hydrophilic cream that forms an emulsion with the secretions of the nasal mucosa, and aqueous formulations were made containing the mucoadhesive polymers polystyrene sulfonate and chitosan. Intranasal pharmacokinetics of the drugs was measured in mice and cotton rats. Lysostaphin formulated in the cream increased nasal retention of the drug as compared to lysostaphin in saline drops. Furthermore, the levels of lysostaphin in the nose after instillation of cream are still above the minimum bactericidal concentration for most bacterial strains. The liquid polymer formulations also resulted in prolonged retention of antibody in the nose, with higher levels as compared to antibody in saline drops.
The results demonstrate that cream and polymer delivery systems significantly decrease the clearance rate of lysostaphin from the nose, thereby enhancing their therapeutic potential for eradicating S. aureus nasal colonization.
5.3.2 TOPICAL DELIVERY OF VITAMIN A (43): -
Burst release as well as sustained release of vitamin A can be obtained by using SLN suspensions. For dermal application burst release and sustain release are taken into consideration. Burst release can be useful to improve the penetration of a drug. Sustained release becomes important with active ingredients that are irritating at high concentrations or to supply the skin over a prolonged period of time with a drug.
Glyceryl behenate SLN were loaded with vitamin A and the release profiles were studied. Franz diffusion cells were used to assess the release kinetic over a period of 24 h. Within the first few hours SLN displayed controlled release. After longer periods of time, the release rate increased and even exceeded the release rate of comparable nanoemulsions. Pure SLN dispersions were characterized by low viscosity.
By considering contrast to membranous vesicles, SLN can also be stably incorporated in convenient topical dosage forms like hydrogels or creams. So in the Franz diffusion cell hydrogels or creams showed a controlled release over 12-18 h. Similar to SLN dispersions an increase in release rate over a 24-h period was found. A good correlation between polymorphic transitions and increased drug release was observed. Sustained release was often related to the metastable beta' polymorph. Thus the release can be controlled with surfactant mixtures or, in the case of the hydrogel and oil/water cream, with humectants or gelling agents.
5.3.3 DELIVERY OF EPIDERMAL GROWTH FACTOR BY TOPICAL ROUTE (44):-
The study investigating the effect of a topical Recombinant human epidermal growth factor (rhEGF) ointment on the rate of wound healing and skin re-epithelialization in a rat full thickness wound model, to verify whether or not the rhEGF treatment affects both myofibroblast proliferation and collagen synthesis in the dermis was carried out when rhEGF was applied topically from the result it was found that, there was significantly enhanced wound closure. A histological examination concluded that the rhEGF treatment increased the number of proliferating nuclear antigen immunoreactive cells in the epidermis layer. In addition, the immunoreactive area of alpha-smooth muscle actin and the expression of prolyl 4-hydroxylase were significantly higher than those of the control group. Overall, a topical treatment of rhEGF ointment promotes wound healing by increasing the rate of epidermal proliferation and accelerating the level of wound contraction related to myofibroblast proliferation and collagen deposition.
5.3.4 TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN (45, 46):-
There are an ever-increasing number of agents that can be used to help patients with neuropathic-based oral and perioral pain problems. A clear advancement in the delivery of such medications is the development of a vehicle-carrier agent (pluronic lecithin organogel) that can penetrate the mucosa and cutaneous tissues and carry the active medication with it to the treatment site. The major problem underlying these treatment strategies is that except for patient testimony and a few studies, there are limited empirical data on the efficacy of most of these new formulations, and additional research is clearly needed. Because of their rapid onset and low side-effect profile, topical medications offer a distinct advantage over systemic administration for those orofacial disorders that are regional, near the surface and chronic and that demonstrate some response such as pain relief to topical or subcutaneous anesthetics.
5.3.5 FOAM DRUG DELIVERY (47): -
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)are less dense,
c)And spread more easily than other topical dosage forms.
Foams may be formulated in various ways to provide emollient or drying functions to the skin, depending on the formulation constituents. Therefore, this delivery technology should be a useful addition to the spectrum of formulations available for topical use; however, as yet, only a few are commercially available. Probably the most convincing argument for the use of foams is ease of use by the patient, and consumer acceptance. Most foam dosage forms used in dermatology to date have incorporated corticosteroids, although some products have also been used to deliver antiseptics, antifungal agents, anti-inflammatory agents, local anesthetic agents, skin emollients, and protectants.
Although there is no clinical evidence that foam formulations are currently superior to other conventional delivery vehicles, these formulations have a clear application advantage and with continued developments in the science of supersaturating technology, it seems certain that foam delivery systems will retain their place in the dermatological and cosmetic armamentarium.
6.QUALITY ASSURANCE AND QUALITY CONTROL OF SEMISOLIDS(2): -
A “PERFECT PRODUCT” requires an organized effort by the entire company to prevent or eliminate errors at every stage in production.
Quality must be built into a drug product during product and process design and it is influenced by the physical plant design, space, ventilation, cleanliness and sanitation during routine production.
It considers, Materials, In process control and Product control which include specifications and the product itself, specific stability procedures for the product, freedom from microbial contamination and proper storage of the product and container, packaging and labeling to ensure that container closer system provide function protection of the product against such factors as moisture, oxygen.
Parameters to be considered during evaluation of semi-solids include raw material specification, in process control and finished product specifications.
6.1 RAW MATERIAL SPECIFICATION (2): -
The FDA current Good Manufacturing Practices [CGMP] covering raw material specification handling procedures are found in the code of Federal Regulations, Title 21 and section 211.42
Sr. no
Test

A.
Raw material name

1.
Structural formula, molecular weight
2.
Chemical name
3.
Item number
4.
Date of issue
5.
Date of superseded, if any, or new material
6.
Signature of writer
7
Signature of approval

B.
Samples

1.
Safety requirement
2.
Sample plan and procedure
3.
Sample size and sample container to be use
4.
Preservation sample requirement

C.
Retest program

1.
Retesting schedule
2.
Reanalysis to be perform to assure identity, strength, quality and purity

D.
Specifications wherever applicable

1.
Description
2.
Solubility
3.
Identity
a.
Specific chemical test
b.
Infrared absorption
c.
Ultraviolet absorption
d.
Melting range
e.
Congealing point
f.
Boiling point or range
g.
Thin layer, paper, liquid or gas chromatoghraphy
4.
Purity and quality
a.
General completeness of solutions, pH, specific rotation, non-volatile residue, ash, acid- insoluble ash, residue on ignition, loss on drying, water content, heavy metals, arsenic, lead, mercury, selenium, sulphate, chloride, carbonates, acid value , iodine value, saponification value
b.
Specific quality tests ,particle size, crystallinity characteristics ,and polymorphic forms
c.
Specific purity tests , related degenerated products
5.
Assay , calculated either on anhydrous or hydrous basis
6.
Microbial limit test, especially for raw materials from natural sources

E.
Test procedure

1.
Compendial USP or NF references
2.
Noncompendial, detailed analytical procedures, weights, dilutions, extraction, normality, reagent, instrumentation used and procedure, if any calculation

F.
Approved suppliers (list of prime suppliers and other approved alternative suppliers, if any)
Table 6.1 : Raw material quality assurance monograph (2)
6.2 IN PROCESS CONTROL (1):-
Processing of semisolids involves mixing, milling, heating and cooling of bulk products. Therefore, it is essential to develop in process control. Some important in process tests are as follows,
1. Complete solubilization (if applicable)
2. pH
3. Viscosity measurement
4. Uniformity of distribution of active ingredients
5. Physical stability
6.Measurement of density or specific gravity.
6.3 FINISHED PRODUCT SPECIFICATIONS (1):-
Most semisolids are heated to high temperature, processed and packaged in a hot or warm liquid state. There is a considerable lapse time until they achieve their final physical state. At this point they should be tested for conformity with final specifications. Test to be perform are as follow.

Fig 6.1 : Pathway for finished product specification
6.3.1 MICROBIAL TEST (28): -
With exception of ophthalmic ointments, topical preparations are not require being sterile. They must meet acceptable standards for microbial contents and preparations that are prone to microbial growth must contain anti-microbial preservatives.
Microbial limits are stated in USP. For example: Betamethasone valerate ointment USP, must meet the requirements of the tests for absence of Staphylococcus aureus and Pseudomonas aeruginosa.
In the USP chapter titled “Microbial Attributes of Non sterile Pharmaceutical Products”, emphasis is placed on strict adherence to environmental control and application of GMP to minimize both type and the number of microorganisms in unsterilised pharmaceutical product.
The USP states that dermatological products of such type should be examined for Pseudomonas aeruginosa and Staphylococcus aureus and those intended for rectal or urethral or vaginal use should be tested for yeasts and molds, common offenders at these sites of application.
6.3.2PHYSICAL TESTS (1, 48): -

Fig 6.2 : Physical tests
Viscosity measurement is done with the help of Brook-field viscometer, Cone and plate viscometer and Penetrometer – for consistency measurement.
Texture analysis:- Stable micro systems have launched a new Q.C. device – Texture analyzerwhich is used to detect,
a)Ointment flow characteristic
b)Ointment consistency
c)Gel strength (12): - Gels have gained wide acceptance as semisolid dosage forms. It has been postulated that the strength rather than the viscosity of a gel layer plays a major role in determining the amount of drug release from hydrophilic matrices. Recent advances have occurred in the development of an optimal apparatus to characterize gel strength. One proposed apparatus consists of a sample holder placed on an electronic microbalance connected to a computer. A probe is lowered into the sample by means of a motor equipped with a speed transformer, and the force required to penetrate the gel is measured. The increase in force with time is a function of the mechanical resistance of the sample to the penetration of the probe. Because the lowering speed is known, the displacement covered by the probe as a function of time is calculated and used to compute the gel-strength parameter or mechanical resistanceof the gel system.
d)Flavour release (49): -A theory of flavour release from gelatin-sucrose gels has been developed based on combined interfacial mass and heat transport. The driving force for flavour release is shown to depend on the bulk melting temperature of the gel, which depends on the gelatin and sucrose concentrations. For gels possessing melting points below the mouth temperature, the driving force for flavour release is the rate at which heat can diffuse into the gels matrix and initiate melting. For harder gels with melting points above mouth temperature the diffusion of sucrose from the surface of the gel into the adjacent saliva phase is the rate limiting step for flavour release, because this lowers the melting temperature of the surface layer. The theoretical model gives good agreement with in vitro release experiments using gelatin gels containing sucrose and dye.
e)Sachet or Tube extrusion force measurement: - Stable micro systems have launched a new Q.C. device that quantifies the force required to extrude the contents from either tube or sachet style packaging. This device allows manufacturers to tests the force required to extrude the content of a sachet or tube at regular intervals over a long period of time, throughout its shelf life and adopt formulation accordingly.
6.3.3 CHEMICAL TESTS (1): -
Chemical tests to be performed include,
a.Chemical potency test
b.Content uniformity test
c.pH measurement
6.3.4 IN-VITRO RELEASE PROFILE TEST (2, 12): -
The principal in vitro technique for studying skin penetration involves use of some variety of a diffusion cell like Franz cell and Flow through cell in which animal or human skin is fastened to a holder and the passage of compounds from the epidermal surface to a fluid bath is measured.
Hairless rats were sacrificed by an overdose of halothane anesthesia. The skin from the dorsal surface was excised, and the adherent fat and subcutaneous tissue were removed. The skin was mounted on Franz diffusion cells with the epidermis facing the donor compartment. The skin permeation studies were performed by the procedure as described under “release studies.”
For the skin retention studies, the donor cell was removed, and the excess formulation was removed from the surface of the skin using a cotton swab. The skin was then washed with 50% ethanol: water and blotted dry with lint-free absorbent wipes. The entire dosing area (0.636 cm2) was collected with a biopsy punch. The epidermis was separated from the dermis, and the tissues were minced using a dissection blade. Where applicable, the stratum corneum (SC) was stripped 20 times using breathable medical tape and the stripped skin was used to conduct permeation and skin retention experiments. Active drug content of epidermis and dermis was extracted using a previously reported method. Briefly, the samples were homogenized and boiled for 10 minutes in solvent (xM). The samples were then centrifuged and the supernatant was collected for analysis of drug by HPLC. The experiments were repeated at least 3 times using the skins from different rats.
6.3.5 INSTRUMENTAL ANALYSIS
6.3.5.1 ANALYSIS OF PHARMACEUTICAL CREAMS USING UV SPECTROPHOTOMETRY (50): -
Solid-phase extraction (SPE) using C-18, diol and ion-exchange sorbents followed by UV spectrophotometric (conventional and derivative mode) assay was applied to the analysis of basic, acidic and neutral drugs commercially available in creams. A representative set of drugs (promethazine, chlorhexidine, benzydamine, ketoprofen, ibuprofen, fentiazac, piroxicam, fluorouracil, crotamiton and hydrocortisone acetate) was selected, and for each drug the appropriate SPE conditions (adsorption, washing and elution) were investigated to obtain a practical and reliable sample clean-up. It was shown that the developed SPE procedures were capable of removing interfering cream components (excipients including preservatives) allowing accurate spectrophotometric analyses to be performed. In some applications, derivative spectrophotometry was advantageous over the conventional absorption mode with respect to higher selectivity and versatility.
6.3.5.2 MODIFIED USP TYPE II DISSOLUTION APPARATUS (10): -
A USP Type II dissolution apparatus was modified for studying the in vitro release of phenol from ointment. It comprised a 200-mL vessel, 2.5 * 1.5 cm paddle, and an Enhancer diffusion cell (VanKel, Cary, NC). The cell contained an adjustable-capacity sample reservoir, a washer for controlling the exposure of the surface area, and an open screw-on cap to secure the washer and membrane over the sample reservoir. The water bath was maintained at 37 C. Filled cells were placed in the bottom of the vessels, and the paddles were lowered to 1 cm above the sample surface. 50 ml of high-performance liquid chromatography–grade filtered water, degassed and prewarmed to 37 0C, was used as the dissolution medium. The system was found to yield reproducible results with good reliability in the data generated.
6.3.5.3 ANALYSIS OF GEL USING FT-NIR TRANSMISSION SPECTROSCOPY (51):-
The objective of this study was to demonstrate the use of transmission Fourier transform near- infrared (FT-NIR) spectroscopy for quantitative analysis of an active ingredient in atranslucent gel formulation. Gels were prepared using Carbopol 980 with 0%, 1%, 2%, 4%, 6%, and 8% ketoprofen and analyzed with an FT-NIR spectrophotometer operated in the transmission mode. The correlation coefficient of the calibration was 0.9996, and the root mean squared error of calibration was 0.0775%. The percent relative standard deviation for multiple measurements was 0.10%. The results prove that FT-NIR can be a good alternative to other more time-consuming means of analysis for these types of formulations.
Topical formulations, such as gels, creams, and ointments, represent a small but significant overall fraction of marketed pharmaceutical products. Most of these formulations present analytical challenges to those who must develop methods to test them. Typically, test procedures for these products require tedious extractions and difficult sample preparation procedures.
Fourier transform near-infrared (FT-NIR) spectroscopy is an analytical technique that has gained popularity in recent years for analyzing raw materials, intermediate products, and finished dosage forms . Among the finished products that have been most often analyzed using NIR spectroscopy are tablets, capsules, and lyophilized materials.
The major strengths of FT-NIR include fast and easy equipment operation, good accuracy and precision, and the potential to perform nondestructive analyses. However, the most attractive advantage of FT-NIR with respect to the analysis of topical formulations is that samples do not typically have to be manipulated before analysis. A literature review showed that FTNIR has not often been used for routine analysis of topical formulations such as gels, creams, and ointments; hence, in this study, quantitative analysis of a clear topical gel formulation containing ketoprofen as the active ingredient was performed using transmission FT-NIR. Carbopol 980 gel was selected for this study because of its wide use as a topical gel in commercial formulations.
6.3.5.4 ANALYSIS OF MULTIPLEXED 2DE GELS: -
The requirements and expectations of 2DE increase, new technologies emerge in a bid to more accurately capture the sometimes small, but significant, changes occurring in proteomics experiments. Therefore a proteomics researcher requires software that is extremely sensitive and still maintains his confidence in the analysis. One such technological jump in 2DE has been the introduction of multiplexed gel-staining methods. Samples are visualized using different fluorescent stains (such as the Cy2, Cy3 and Cy5 stains commonly used) and run on the same physical two-dimensional gel. Multiple images are then produced allowing the analysis of each sample to be performed.
7. PACKAGING OF NOVEL SEMISOLIDS (1, 28): -
Most semisolid products are manufacture by heating and are filled into the container while cooling still in the liquid state. It is important to established optimum pour point, the best temperature for filling and set or congealing point, the temperature at which the product become immobile in the container.
Topical dermatological products are packed in either jar or tubes whereas ophthalmic, nasal, vaginal and rectal semisolid products are almost always packed in tubes.
The specific FDA regulation pertaining to drug products state that,
“Container closures and other component part of drug packages, to be suitable for that intended use must not be reactive, additive or absorptive to the extent that identity, strength, quality or purity of drug will be affected”
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 e.g. 20 0 C as well as under accelerated stability testing condition e.g. 40 - 50 0 C.
Ointment jars are made up of clear or opaque glass or plastic. Some are colored green, amber or blue. Opaque jars are used for light sensitive products, are porcelain white, dark green or amber. Commercially available empty ointment jars vary in size from about 0.5 ounce to 1 pound. In commercial manufacture and packaging of topical products the jars and tubes are first tested for compatibility and stability for the intended product. This includes stability testing of filled containers. Tubes use to package topical pharmaceutical products are gaining in popularity since they are they are light in weight, relatively inexpensive, convenient for use, compatible with most formulative component and provide protection against external contamination
Ointment tubes are made of aluminum or plastic. When the ointment is use for ophthalmic, rectal, vaginal or nasal application, they are packed with special applicator tips.
The multiple dose tube used for pharmaceutical has conventional continuous thread closure. Single dose tube may be prepared with a teraway tip. Meter dose, temper evident and child resistant closures are also available. Standard size of empty tubes has capacity of 1.5, 2, 3.5, 5, 15, 30, 45, 60 and 120 gm.
Ointment, creams and gels are most frequently packed in 5, 15 and 30 gm tubes. Ophthalmic ointments typically are packed in small aluminum or collapsible plastic tubes holding 3.5 gm of ointment
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