Based On Electrokinetic Nature Of Solid Particles

Published Date: 02 Nov 2017

The suspension is often selected as a pharmaceutical dosage form when drug is insoluble in water and aqueous fluids at the dosage required for administration. Suspensions minimize drug degradation and used to mask the unpleasant taste of drug which is particularly useful for products intended for pediatric and geriatric patients .

The bioavailability of drug is assumed to increase in the following order.

Solutions>Suspensions>Capsules>Compressed tablets>Coated tablets.

Large surface area of dispersed drug may help ensure a high degree of avilability for absorption.

1.2.1 Desirable attributes of a suspension

The dispersed particles should be small and uniform; they should not settle fast.

Suspended material should not settle readily at bottom of container. Should be redispersible into a uniform mixture upon shaking and must not cake.

Physical charecteristics such as particle size and viscosity should remain fairly constant throughout the shelf life of product.

Constant particle size distribution.

Suspension viscosity must promote free and even flow from container.

Resuspension should produce a homogenous mix of drug particles such that same amount of drug can be removed repeatedly.

It should be safe,effective, stable ,pharmaceutically elegant during its shelf life.

Resistance to microbial contamination.

1.3. Classification

Based On General Classes

Oral suspension (normally contains 125 to 500mg per 5ml of solid material)

Externally applied suspension (concentration of dispersed phase exceed20%)

Parenteral suspension (concentration of solid particles ranges from 0.5-30%)

Based On Proportion Of Solid Particles

Dilute suspension (2 to10%w/v solid)

Concentrated suspension (50%w/v solid)

Based On Electrokinetic Nature Of Solid Particles

Flocculated suspension

Deflocculated suspension

Based On Size Of Solid Particles

Colloidal suspension (< 1 micron)

Coarse suspension (>1 micron)

Nano suspension (10 ng)

Suspensions contribute to pharmacy and medicine by supplying insoluble and often distasteful substances in a form, which is pleasant to the taste; by providing a suitable form for the application of dermatological material to skin and sometimes to the mucous membranes; and for the parentral administration of insoluble drugs. Suspensions are an ideal dosage form for those patients who have difficulty in swallowing tablets or capsules. This factor is of particular importance in the administration of drugs to children and elderly patients.

Almost all suspension systems separate on standing. The formulator’s main concern therefore, is not necessarily is to try to eliminate separation but rather to decrease the rate of settling and to permit easy re-suspendability of any settled particulate matter. A satisfactory suspension must remain sufficiently homogenous for at least the period of time necessary to remove and administer the required dose after shaking its container. The major challenges to be faced in the formulation of suspensions are: -

The diffusion or release of drug into suspending vehicle during storage.

The interaction between dispersing vehicle and dispersed phase during storage

An ideally inert suspending medium is yet to be found, into which drug do not diffuse during storage and which does not change important properties of formulation during storage10.

Advantages

A suspension is an ideal delivery system for insoluble and bitter tasting drugs.

Suspensions allow masking of taste and thus improve patient compliance.

Suspensions offer better chemical stability of drugs.

Drugs from suspensions are more readily bioavailable than from a tablet or a capsule.

Suspensions in non aqueous solvents provide a useful form of administration for drugs that degrade rapidly in aqueous solution.

Suspensions are often effective than tablets and capsules in pediatric and geriatric patients because they are easy to swallow.

Dose flexibility,such as one half or one third of a dose is more convenient with suspensions than with solids

Disadvantages

Physical stability,sedimentation and compaction can causes problems.

If suspension is bulky care must be taken during handling and transport.

It is difficult to formulate.

Uniform and accurate dose can not be achieved unless suspension are packed in

unit dosage form.

1.3.2. Bioavailability from suspensions

Oral bioavailability of a drug depends on the nature and type of dosage form. The relative rate at which a drug from a dosage form is presented to body depends upon the complexity of dosage form. Suspensions of a drug may be expected to demonstrate improved bioavailability compared to the same drug formulated as a tablet or capsule. This is because the suspension already contain discrete drug particles, where as tablet must invariably undergo disintegration in order to maximize the necessary dissolution process. Suspensions afford a better bioavailability on account of greater surface area. Important factors in the bioavailability of a drug from suspensions include particle size,polymorphism, viscosity of medium, suspending agent11,12

1.3.3. Stability of suspension

Particles in the dispersion exhibit repulsive as well as attractive forces. When the forces of repulsion are greater, the particles remain apart. However when the Vander wall’s attraction forces exceed that of electrostatic repulsive forces, the particles come together when these particles are held strongly it is referred to as clusters or aggregates and it is the aggregation of particles into a solid mass that settles into the bottom of the container, which is referred as caking. When the particles are held together in a loose open structure in suspension, they are referred as flocks and the system is said to be in a state of flocculation. The light fluffy flocks settle rapidly in a suspension to form loosely arranged sediment, which is easy to redisperse. Conversely the individual particles in a well-dispersed deflocculated suspension settle more slowly but have a tendency to form a cake that is difficult to redisperse13.

The concept of controlled flocculation is largely attributed to Haines and Martin.

Different methods of producing flocculation may be adopted which include use of electrolyte, detergents, polymer, and liquids as flocculating agents.

The various methods that are available to assess the stability of suspensions are14

Viscosity and thixotropy

Rate of settling measurement

Measurement of particle size

Radio-isotopic methods

Electro kinetic measurement.

1.4 FORMULATION OF SUSPENSION

The criteria for selecting ingredients are based both on suitability for reconstitution and on the physical type of powder mixture desired.

Drug: Nearly all drugs formulated as reconstitutable oral suspensions are antibiotics mainly penicillin derivatives. eg.Amoxycillin trihydrate, Ampicillin, Cephalexin, Dicloxacillin sodium.

Suspending agent: Suspending agents are used to impart increased viscosity and retard sedimentation after reconstitution. Factors to be considered during selection of suspending agent include chemical compatability with all ingredients, especially the drug, flow behaviour, maximum viscosity, pH range, ionic charge, range of useful concentration.

Suspending agents suitable for use in suspensions for reconstitution

Agent Concentration range(%)

Acacia 2.0

Carboxy methyl cellulose sodium 1-2

Povidone 5-10

Silicon dioxide colloidal 0.25-1

Tragacanth 0.2-4

Xanthan gum 0.3-3

Acacia and traganth have been used as suspending agents but they cause batch variation in color viscosity,gel strength and hydration rate.

Combination of microcrystalline cellulose and sodium carboxymethyl cellulose is a common suspending agent.They are anionic and incompatible with many cationic ingradients.

Xanthan gum is a common suspending agent in suspension for reconstitution.Its solution viscosity is practically independent of ph and temperature.

Sweetener:

Sweetener is a significant component of suspensions for reconstitution.Drugs frequently have a bitter taste .Sweeteners can mask the unfavourable taste and enhance patient acceptance in the pediatric population.Any increased viscosity as a result of the sweetener aids suspension of the drug particles.Sucrose serve as a sweetener, suspending agent and diluent in the dry mixture.Other sweeteners include mannitol, dextrose, aspartame and sodium saccharin.Aspartame has fair acid stability but poor heat stability.

Wetting agent:

Hydrophillic drugs are readily wetted by an aqueous vehicle.These drugs can be incorporated into suspensions with out use of a wetting agent.Many drugs in suspension, however are hydrophobic, they repel water and are not easily wetted.

Surfactants are commonly used to aid in the dispersion of hydrophilic drugs.Formulator selects the appropriate wetting agent for optimum dispersion of drug at the lowest efective concentration.

Polysorbate 80 is a common wetting agent.It is nonionic and is chemically compatible with both cationic and anionic excipients and drugs.

Another common wetting agent is sodium lauryl sulphate.This agent is anionic and may be incompatible with cationic drugs.

Buffers:

Buffers are used to maintain optimum pH for all ingradients.Suspensions pH is often adjusted to ensure that drug remains insoluble.The polymeric suspending agents have greatest viscosity at the ph of their maximum solubility.The suspending agent should be stable at the pH of the system for the shelf life of the product .Certain preservatives such as sodium benzoate, are most effective at low pH values in which the molecule is unionized.Sodium citrate is a common buffer used in the suspensions for reconstitution.

Preservatives:

Preservatives are required in the most suspensions because the suspending agents and sweeteners are often good growth media for micro organisms.The choice of preservatives in suspensions for reconstitution is limited because most of these ingradients require extended time periods for dissolution at room temperature.Examples of these poorly soluble preservatives that are not recommended include sorbic acid and methyl or propyl hydroxyl benzoates (parabens).Other common preservatives include sodium benzoate and sodium propionate.

Flavours:

Flavours enhance patient acceptability of product.They are important in the products that are intended for pediatric patients.Both natural and artificial flavours are used.Additional flavours include orange, menthol, raspberry, pineapple etc.

Colorants:

Colorants are intended to provide a more aesthetic appearance to the final suspension.As relatively large cations or anions,these agents may be chemically incompatible with other ingradients.Common water soluble colorants include FD&C regd no.4 and FD&C yellow no.6

Anticaking agents:

Common problem in dry mixtures is poor powder flow and caking.This is often caused by powder agglomeration due to moisture uptake.As a desicant,these agents remove moisture from the dry mixture to facilitate good powder flow and prevent caking.In addition anticaking agents separate the dry particles to inhibit fusion.They also

provide thermal insulation, screen and insulate static charge conditions and are chemically inert.

COLON DRUG DLIEVERY SYSTEM

Targeted drug delivery into the colon is highly desirable for local treatment of a variety of bowel diseases such as ulcerativecolitis, Crohn’s disease, amebiosis, colonic cancer, local treatment of colonic pathologies, and systemic delivery of protein and peptide drugs.The colon specific drug delivery system (CDDS) should be capable of protecting the drug en route to the colon i.e. drug release and absorption should not occur in the stomach as well as the small intestine, and neither the bioactive agent should be degraded in either of the dissolution sites but only released and absorbed once the system reaches the colon The colon is believed to be a suitable absorption site for peptides and protein drugs for the following reasons; Less diversity, and intensity of digestive enzymes Comparative proteolytic activity of colon mucosa is much less than that observed in the small intestine. And finally, because the colon has a long residence time which is up to 5 days and is highly responsive to absorption enhancers. Oral route is the most convenient and preferred route but other routes for CDDS may be used. Rectal administration offers the shortest route for targeting drugs to the colon.

However, reaching the proximal part of colon via rectal administration is difficult. Rectal administration can also be uncomfortable for patients and compliance may be less than optimal Drug preparation for intrarectal administration is supplied as solutions, foam, and suppositories. The intrarectal route is used both as a means of systemic dosing although these drugs are absorbed from the large bowel, it is generally believed that their efficacy is due mainly to the topical application. The concentration of drug reaching the colon depends on formulation factors, the extent of retrograde spreading and the retention time. Foam and suppositories have been shown to be retained mainly in the rectum and sigmoid colon while enema solutions have a great spreading capacity.

Because of the high water absorption capacity of the colon, the colonic contents are considerably viscous and their mixing is not efficient, thus availability of most drugs to the absorptive membrane is low. The human colon has over 400 distinct species of bacteria as resident flora, a possible population of up to 1010 bacteria per gram of colonic contents. Among the reactions carried out by these gut flora are azoreduction and enzymatic cleavage i.e. glycosides. These metabolic processes may be responsible for the metabolism of many drugs and may also be applied to colon- targeted delivery of peptide based macromolecules such as insulin by oral administration.

ANATOMY OF THE COLON

The location of the parts of the colon is either in the abdominal cavity or behind it in the retroperitoneum. The colon in those areas is fixed in location.

The haustra of the colon are the small pouches caused by sacculation, which give the colon its segmented appearance.

The taenia coli runs the length of the large intestine. Because the taenia coli are shorter than the intestine, the colon becomes sacculated between the taenia, forming the ulcerative colitis.

Large intestine.

Blood supply and lymphatics

Arterial supply to the colon comes from branches of the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA).Flow between these two systems communicates via a "marginal artery" that runs parallel to the colon for its entire length.

Venous drainage usually mirrors colonic arterial supply, with the inferior mesenteric vein draining into the spleen vein, and the superior mesenteric vein joining the splenic vein to form the hepatic portal vein that then enters the liver. Lymphatic from the entire colon and proximal two-thirds of the rectum is to the par aortic lymph nodes that then drain into the cisterna chyli. The lymph from the remaining rectum and anus can either follow the same route, or drain to the internal iliac and superficial inguinal nodes. The pectinate line only roughly marks this transition

By segment

Ascending colon

The ascending colon, on the right side of the abdomen, is about 25 cm long in humans. It is the part of the colon from the cecum to the hepatic flexure (the turn of the colon by the liver). It is secondarily retroperitoneal in most humans. In ruminant grazing animals, the cecum empties into the spiral colon.

Transverse colon

The transverse colon is the part of the colon from the hepatic flexure to the splenic flexure (the turn of the colon by the spleen). The transverse colon hangs off the stomach, attached to it by a wide band of tissue called the greater omentum. On the posterior side, the transverse colon is connected to the posterior abdominal wall by a mesentery known as the transverse mesocolon.

The proximal two-thirds of the transverse colon is perfused by the middle colic artery, a branch of SMA, while the latter third is supplied by branches of the IMA.The "watershed" area between these two blood supplies, which represents the embryologic division between the midgut and hindgut, is an area sensitive to ischemia.

Descending colon

The descending colon is the part of the colon from the splenic flexure to the beginning of the sigmoid colon. The function of the descending colon in the digestive system is to store food that will be emptied into the rectum. It is retroperitoneal in two-thirds of humans. In the other third, it has a (usually short) mesentery. The arterial supply comes via the left colic artery.

Sigmoid colon

The name sigmoid means S-shaped. The sigmoid colon is the part of the large intestine after the descending colon. The walls of the sigmoid colon are muscular, and contract to increase the pressure inside the colon, causing the stool to move into the rectum.

PROPERTIES OF GASTRO –INTESTINAL TRACT

Table no:1

LOCATION

PH

STOMACH

Fasted

Fed

1.5-2.0

3.0-5.0

5.0-6.5

LARGE INTESTINE

Right colon

Left colon

Mid colon

5.5-7.3

6.6-7.0

6.6

7.2

SMALLINTESTINE

Jejunum

Ileum

6.0-7.5

6.4-6.7

6.7-7.5

Table no:2

REGION OF GIT

PROPERTY

MEASURED VALUE

Total GIT

Surface area

2-10cm

Small intestine

Length

20-30cm

Colon

Length

20-40cm

Large intestine

Length

6-7cm

Small intestine

Large intestine

Internal diameter

3-4cm

6cm

Stomach

Duodenum

Jejunum

Colon

PH

1-3.5

5-7

6-7

7

Colon

Redox potential

-415

FACTORS EFFCTING THE COLON DRUG DELIVERY

Gastrointestinal transit

The drug delivery systems first enter into stomach and small intestine via mouth and then reach colon.The nature and PH of gastric secretions and gastric mucosa influence the drug release of absorption.

Small intestine transit

The small intestinal transit is not influenced by the physical state, size of the dosage from and the presence of food in the stomach .The mean transit time of the dosage form is about 3-4 hours to reach the ileocecal junction and the time period is consistent. The dosage from exposed to enzymes, present in the small intestine .The release of drugs from the prodrug based systems and stability of peptides can be affected by bacterial contents in the ileum.

Colonic transit

The bioavailability of drugs, released from the dosage forms can be influenced by the colonic transit time. various factors like gender and size of the dosage form, and physiological conditions such as stress, presence of food and diseased state influence the colonic transit time.

Gastric emptying

In fasted state, gastric emptying is fastest and most consistent. Emptying completes from 5-10 min upto 2hrs, depending on phase of the stomach at the time of drug administration. It can be slowed by fed state. For drug delivery to the systemic vasculature, small transit time in stomach to reduce random distribution of particulate drug through intestine is preferable.

Stomach and intestinal PH

Generally,the release and absorption of orally administered drugs are influenced by the gastro intestinal PH.The PH gradient in the GIT is not in an increasing order. In stomach the PH is 1.5,-2.0,2.0-6.0 in fasted and condition ,respectively.The acidic PH is responsible for the degradation of various PH sensitive drugs and enteric coating may prevent it.

Colonic microflora and enzymes

The human alimentary canal is highly populated with bacteria and other micro flora at the both ends, that is the oral cavity and the colon /rectum. Micro organisms of the oral cavity, normally do not affect oral drug delivery systems, however, gut microflora of the colon offers a number of implications in the health and the treatment of diseases such as IBD.

Colonic absorption

The surfaces areas of the colon is much less compared to small intestine and hence not ideally suited for absorption, despite this limitation ,the colon is considered for drug delivery because the environment is devoid of endogenous digestive enzymes other than residence time of colon can be as long as 10-24hrs.

Gastro intestinal disease state

Most of the diseases associated with nausea and vomiting may expel the drug content. In antibiotic –related colitis condition, plaque formation on the mucosa may interfere with the absorption of the drugs. Antibiotic induced depression of intestinal motility, particularly the muscaris, may enhance antibiotic–resistant bacterial growth leading to colitis.

Pharmaceutical factors

Drugs, which show poor absorption from the stomach or intestine including peptide drugs, are most suitable for colonic specific drug delivery systems. The drugs used in the treatment of IBD, Ulcerative colitis, diarrhea are ideal candidates for local colon drug delivery. sulphasalazine and 5-ASA are widely used for drugs for the treatment of IBD and the other drugs include dexamethasone, prednisolone, hydrocortisone and budenoside.

COLON DISORDERS

INFLAMMATORY BOWEL DISEASE

In medicine, inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.

The main forms of IBD are Crohn's disease and ulcerative colitis (UC) and collangenous colitis.

The main difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Finally, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions.

Rarely, a definitive diagnosis of neither Crohn's disease nor ulcerative colitis can be made because of idiosyncrasies in the presentation. In this case, a diagnosis of indeterminate colitis may be made. Although a recognized definition, not all centres refer to this.

Colon cancer:

Stages of cancer.

Cancer occurs when cell becomes abnormal such type of cells divide and form mass of tissue which causes the tumors in the colon arise from the large intestine.

The spread of colon to the other species of organs is called as metastasis.

Malignant tumors of large intestine which mainly causes the severity of the disease.

The people suffering from colon cancer and the percentage are shown in the following table:

Table no:3

COLON CANCER

PERCENTAGE

In men

10%

In women

11%