Overview Of Pharmaceutical Targeted Tablet

Targeted drug delivery system (TDDS), sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue.

For most therapeutic agents, only a small portion of the medication reaches the organ to be affected, such as in chemotherapy where roughly 99% of the drugs administered do not reach the tumor site. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues.

Targeted tablet

When implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease.

Advantages Of Targeted Drug Delivery System (TDDS)

1. Reduction in the frequency of the dosages taken by the patient

2. Having a more uniform effect of the drug

3. Reduction of drug side-effects

4. Reduced fluctuation in circulating drug levels

Disadvantages Of Targeted Drug Delivery System (TDDS)

1. High cost, which makes productivity more difficult

2. Reduced ability to adjust the dosages

Kinds Of Targeted Drug Delivery System

There are two kinds of targeted drug delivery: active targeted drug delivery and passive targeted drug delivery.

Active Targeting

There are several ways that active targeting can be accomplished. One way to actively target solely diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted. Utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor.

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Active targeting can also be achieved by utilizing magnetoliposomes, which usually serves as a contrast agent in magnetic resonance imaging. Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process.

Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH.

Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is hypoxia, which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors.

Passive Targeting

In passive targeting, the drug's success is directly related to circulation time. By adding polyethylene glycol (PEG) to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic. The particles obtain this property due to the hydrophobic interactions that are natural to the reticuloendothelial system (RES), thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time. To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.

By utilizing both passive and active targeting able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials

Delivery Vehicles

There are different types of drug delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, nano-particle drug carriers, dendrimers, etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic, biodegradable, and must avoid recognition by the host's defense mechanisms.

Liposomes

Liposomes are non-toxic, non-hemolytic, and non-immunogenic even upon repeated injections; they are biocompatible and biodegradable and can be designed to avoid clearance mechanisms [reticuloendothelial system (RES)], renal clearance, chemical or enzymatic inactivation, etc.

The only problem to using liposomes in vivo is their immediate uptake and clearance by the RES system and their relatively low stability in vitro. To combat this, polyethylene glycol (PEG) can be added to the surface of the liposomes. Increasing the mole percent of PEG on the surface of the liposomes by 4-10% significantly increased circulation time in vivo from 200 to 1000 minutes.

Micelles And Dendrimers

They are prepared from certain amphiphilic copolymers consisting of both hydrophilic and hydrophobic monomer units. They can be used to carry drugs that have poor solubility.

Biodegradable Particles

Biodegradable particles have the ability to target diseased tissue as well as deliver their payload as a controlled-release therapy.

Artificial DNA Nanostructures

Nucleic acid logic circuits that could potentially be used as the core of a system that releases a drug only in response to a stimulus such as a specific mRNA have been demonstrated. In addition, a DNA "box" with a controllable lid has been synthesized using the DNA origami method.

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Types Of Targeted Tablet

Under this category there are two types of tablets. They are gastro retentive and target colon tablets.

GastroRetentive Tablet

Used when active pharmaceutical ingredient (API) release is desired in the stomach. There occurs a quick elimination of certain drugs that have been absorbed from the gastrointestinal tract (usually having short half-lives), from the circulatory system due to which frequent dosing is required. To sort out this matter, innovative method gastroretentive drug delivery systems are incorporated.

Advantages Of Gastroretentive Tablet

1. Increase in bioavailability and curative efficiency of drugs

2. Economic usage of dosage reducing cost

3. Minimised factor of risk in resistance in antibiotics owing to stabilised therapeutic levels over prolonged periods removing fluctuations

3. Optimised release in case of short half-life drugs, causes flip flop pharmacokinetics

4. Ensures patient compliance and adherence with reduced dosage frequency

5. These are efficient in repairing stomach and 

small intestine related problems as the drug is available for local therapy in these organs

6. This method provides with a systematic and controlled drug delivery system which minimises chances of drug over exposure at the diseased site

7. Providing a narrow curative index, the gastroretentive dosage forms minimises variance in concentrations of drugs and effects

8. As the system provides with controlled rates of fluctuation, a wider array is provided for selectivity in receptor activation

Disadvantages Of Gastroretentive Tablet

1. Need for increased level of fluids in the stomach

2. Unsuitable for such drugs as:

i. Problematic with solubility in gastric fluid

ii. Causing G.I irritation

iii. Inefficient in acidic environment

3. Drugs intended for selective release in the colon

4. Unpredictable adherence owing to state of constant renewal of mucus wall of stomach

5. GRDDS is fed into the system after the meal as time of stay in stomach depends on digestive state

6. The ability of the drug to remain in the stomach depends upon the subject being positioned upright

7. Hydrogel based swelling system takes longer time to swell

8. Upon multiple administrations, size increasing drug delivery systems pose the threat to life owing to possible hazard of permanent retention in stomach

9. Superporous systems having drawback like problematical storage of much easily hydrolysable, biodegradable polymers

Drugs Suitable For Gastroretentive Tablet

1. Drugs acting locally in the stomach

2. Drugs with narrow absorption window in the GIT

3. Drugs having unstable properties in the intestinal or colonic environment

4. Drugs caused imbalance of normal colonic microbes

5. Drugs having low solubility at high pH value

Unsuitable Drug Candidates

1. Drugs having very limited acid solubility

2. Drugs that exhibits instability in the gastric environment

3. Drugs that are used for selective release in the colon

Approaches For GRDDS

The following methods have been devised to improve the period of retainment of oral dosage form in the stomach viz. floating system, swelling and expanding system, bioadhesive system, high density system and other delayed gastric emptying devices.

a. Floating Tablets

These are designed to prolong the residence time of the dosage form within the GI tract. This not only prolongs GI residence time but also does so in an area of the GI tract that would maximize drug reaching its absorption site in solution and hence, ready for absorption. These are low density tablets. It can expand in gastric environment. Floating in diarrhoea to keep the drug in a floating condition in the stomach to get a relatively better response. Controlled delivery of drugs. It minimizes the mucosal irritation by releasing drug slowly.

Used in treatment of gastrointestinal disorders such as gastro esophageal reflux. Ease of administration and better patient compliance.

Based on the buoyancy mechanism, floating systems are classified as follows: 

I. Effervescent systems

II. Non-effervescent systems

Effervescent Systems (Gas Generating Systems)

Gas bubble generation helps to achieve floatability. They are created in a manner that upon contact with gastric contents CO2 is released finally entrapping in swollen hydrocolloids, that makes dosage forms buoyancy.

These systems are further classified as below:

A. Volatile Liquid Containing System: This system comprises dual chambers having an impermeable, pressure responsive, movable bladder separation. The former chamber has drugs and the latter has volatile liquid. To sustain the GRT of a drug delivery system an inflatable chamber has to be incorporated that carries a liquid e.g. ether, cyclopentane. It turns to gaseous form at body temperature causing inflation of the chamber in the stomach. It may contain a biodegradable plug, made of polyvinyl alcohol, polyethylene, etc. This plug gradually dissolves making the chamber release gas and to collapse after a specific duration to allow spontaneous release of the inflatable systems from the stomach. The drug continues to release as the device inflates.

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These systems are further classified as below:

a. Intragastric floating gastrointestinal drug system

b. Inflatable gastrointestinal delivery system

c. Intragastric-osmotically controlled drug delivery system

B. Matrix Tablets: It can be formulated in a single layer matrix tablet by implementing bicarbonates in the matrix forming hydrocolloid gel agent or in a dual layer matrix along with gas generating matrix together as an individual layer. The drug acts as the second layer. There is a possibility of a triple layer matrix tablet. However now the gas generating matrix is one layer and rest two are drug layers 

C. Gas Generating Systems

a. Floating capsules

b. Floating pills

c. Floating system with ion exchange resins

Non-effervescent Systems

The non-effervescent floating dosage forms have swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymer acrylate, and polystyrene. Its creation has a simplistic approach i.e. mixing of drug with the gel, followed by swelling by coming in contact with gastric fluid after oral administration and thus maintaining a relative integrity of shape and keeping a bulk density less than one (<1).

The dosage form gains its buoyancy owing to air trapped in the swelled up matrix. This swollen up matrix reserves drugs and maintains sustained drug release via gelatinous mass. Hydroxypropyl methylcellulose (HPMC), polyacrylate, polyvinyl acetate, carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates, are the most commonly used excipients.

These systems are further classified as below:

A. Hydrodynamically balanced systems

B. Microballoons/hollow microspheres

C. Alginate beads

D. Layered tablets divided into;

a. Single layered floating tablets

b. Double layered floating tablets

b. Non-floating Systems

Non- floating systems are a class of gastroretentive drug delivery systems which do not float but remain in the stomach for a prolonged time period. These systems are further classified as below;

A. Bioadhesive systems

B. Swelling systems

C. High density systems

D. Expandable systems

E. Magnetic systems 

F. Raft forming system 

G. Superporous hydrogel systems

Colon Targeting Tablets

It provides a desired drug concentration in the body by delivering a therapeutic amount of drug to a target site i.e. colon. It is suitable and required for the drugs having instability, low solubility, and short half-life, a large volume of distribution, poor absorption, low specificity, and therapeutic index. The pH in this region (colon) varies from 6.4-7 and presence of microbial flora plays an important role in drug release.

Various mechanisms adopted for drug release in this area are: coating with pH sensitive polymer, biodegradable polymer which are sensitive to colonic bacteria, bio-adhesive polymer and redox sensitive polymers.

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It provides delivery of drugs accurately into the lower GI tract (by avoiding the drug release in upper GIT), which occurs primarily in the large intestine (i.e. colon). 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 and for the delivery of topically active drug to the large intestine.

Primary Approaches For CDDS

a. pH Sensitive Polymer Coated Drug Delivery to the Colon

The pH range of the human body varie. pH of the stomach during fasting is 1-2 and increases after eating. The pH of the rest of the digestive system are different including that of the colon. Use of pH dependent polymers is based on these differences in pH levels. The polymers described as pH dependent in colon specific drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises.

The main disadvantage is that although a pH dependent polymer can protect a formulation in the stomach, and proximal small intestine, it may start to dissolve in the lower small intestine, and the site-specificity of formulations can be poor. The decline in pH from the end of the small intestine to the colon can also result in problems, lengthy lag times at the ileo-cecal junction or rapid transit through the ascending colon which can also result in poor site-specificity of enteric-coated single-unit formulations.

b. Delayed (Time Controlled Release System)

Release Drug Delivery to Colon Time controlled release system (TCRS) such as sustained or delayed release dosage forms are also very promising drug release systems. However, the disadvantages of this system are:

1. Gastric emptying time varies markedly between subjects or in a manner dependent on type and amount of food intake

2. Gastrointestinal movement, especially peristalsis or contraction in the stomach would result in change in gastrointestinal transit of the drug.

3. Accelerated transit through different regions of the colon has been observed in patients with the IBD, the carcinoid syndrome and diarrhea, and the ulcerative colitis

c. Microbially Triggered Drug Delivery To Colon

Because of the presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery seems to be a more site-specific approach as compared to other approaches. These polymers shield the drug from the environments of the stomach and small intestine, and are able to deliver the drug to the colon. On reaching the colon, they undergo assimilation by micro-organism, or degradation by enzyme or break down of the polymer backbone leading to a subsequent reduction in their molecular weight and thereby loss of mechanical strength. They are then unable to hold the drug entity any longer.

Other Approach

1. Polysaccharide Based Delivery Systems

2. Azo-Polymeric Prodrugs

3. Prodrug Approach for Drug Delivery to Colon

Newly Developed Approaches for CDDS

1. Pressure Controlled Drug-Delivery Systems

2. Novel Colon Targeted Delivery System (CODESTM)

3. Osmotic Controlled Drug Delivery (ORDS-CT)

Advantages Of Colon Targeting Tablet

1. The site specific delivery of drugs to lower parts of the GI tract is advantageous for localized treatment of several colonic diseases, mainly inflammatory bowel disease, irritable bowel syndrome, colon cancer

2. Used in treatment of nicotinic addiction

3. Useful for the delivery of proteins, peptides which are being delivered by injections

4. Delayed mechanisms are designed to improve the efficacy of the drug by concentrating the drug molecules where they are needed the most, minimize the potential side effects and drug instability

5. Used in direct treatment at disease site, low dosing and less systemic side effects

6. Molecules that are poorly absorbed in the upper gut, such as peptides, proteins may be better absorbed from the lower GIT

7. The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease

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8. The colon is having high water absorption capacity, the colonic contents are considerably viscous and thus availability of most drugs to the absorptive membrane is low

9..The metabolic processes like azoreduction and enzymatic cleavage takes place in the colon which is responsible for the metabolism of many drugs and peptides like insulin

Disadvantages Of Colon Targeting Tablet

1. As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time and increased responsiveness to absorption enhancers; however, the targeting of drugs to the colon is very complicated

2. Due to its location at the distal portion of the alimentary canal, the colon is particularly difficult to access

3. There is a wide range of pH values and different enzymes present throughout the GI tract, through which the dosage form has to travel before reaching the target site, further complicating the reliability and delivery efficiency

4. Successful delivery through this site also requires the drug to be in solution form before it arrives in the colon or, alternatively, it should dissolve in the luminal fluids of the colon, but this can be a limiting factor for poorly soluble drugs as the fluid content in the colon is much lower and it is more viscous than in the upper part of the GI tract

5. The stability of the drug is also a concern and must be taken into consideration while designing the delivery system. The drug could potentially bind in a nonspecific manner to dietary residues, intestinal secretions, mucus or fecal matter.The resident microflora could also affect colonic performance via metabolic degradation of the drug

6. Lower surface area and relative ‘tightness’ of the tight junctions in the colon can also restrict drug transport across the mucosa and into the systemic circulation