Pulsincap Technology in Colon Targeted Drug Delivery: A Novel Approach for Site-Specific and Chronotherapeutic Drug Release

Colon targeted delivery of drug/ involves administering medications in such a manner that the formulation passes through the upper gastric system without any change in the drug, which then disintegrates and absorbs in the colon. Crohn's (CD), ulcerative colitis (UC), and Irritable Bowel Syndrome (IBS) are examples of GI disorders that require the medicine to work locally.^1,2. There will be no medication loss with colon-targeting drug delivery systems, and the dosage will reach the intended site with a greater concentration and less systemic adverse effects since the drug will dissolve and absorb in the colon. Colonic mucosa enhances medicine absorption, especially proteins and peptides. The colonic contents have a lengthy retention duration of up to five days, making the colon an ideal organ for medication absorption.³. There are two techniques to colon targeting: oral and rectal. While the oral route is more convenient and commonly accepted by patients, and a broad range of tailored formulations may be generated via oral route, rectal route is not the preferred option for the proximal region of the colon since the medicine cannot reach the specific targeted areas. ⁴. Factors influencing the success of colon targeting formulations include the drug's physiochemical characteristics, the kind of delivery device, gastrointestinal transit duration, and the association among the medication and gastrointestinal contents. Drug transport to the colon can be made more efficient by either stopping the drug's release or shielding it from escape in the small intestine and stomach. This approach is used to create delayed drug delivery for a long period, with lag time till formulation reaches the colon.⁵. Pharmaceutical formulations intended for use in colon targeting are usually created in the form of liquids, foam, and suppositories. ⁶. The foam and suppository are retained in the rectum and sigmoid colon, whereas enema (solutions) have a greater spreading property, demonstrating medications and dose forms for various colon disorders, as well as their route of absorption.

Drug absorption process in the colon.

(CTDDS) is designed to obtain the appropriate and effective medication concentration in the colon while keeping the formulation intact in the small intestine⁷. Most medications follow either transcellular or paracellular routes. Lipophilic medication molecules permeate cell membranes to go through transcellular routes. In the paracellular route, hydrophilic medicines flowed between cell junctions. A percentage of the medicine is absorbed in the small intestine due to the existence of well-defined villi, which the colonic mucosa lacks. The presence of this villi increases medication absorption in the small intestine, but the absence of this villi makes the large intestine unsuitable for drug absorption by traditional formulations; therefore, the need for colon-targeted drug delivery methods to ⁸. Although drug absorption occurs largely in the small intestine, the colonic mucosa has a tighter epithelium, which leads to reduced paracellular permeability and a greater resistance to electricity of the epithelium of the colonic mucosa as compared to the small intestine ⁹. Because the colon has a shorter transit time, medicines can linger in the colon for extended periods of time by coming into touch in the colonic mucosa. Furthermore, the colon's substance is more viscous, resulting in a slower dissolution rate and decreasing medication transportation through the colon. These qualities vary depending on the length and fluid content for the colon. Drugs are theoretically absorbed throughout the GIT; however, they are more typically absorbed in the proximal jejunum and duodenum in the small intestine. The delayed-release dose forms are developed to achieve effective medication release in the colon. This colon-targeted formulation exhibits a "burst release," a sustained or protracted release, and a targeted release. The two basic types of colon targeted medication formulations are one piece colon targeted drug delivery systems and multi-particulate dosage form systems. The downside of a single CTDDS is that it finds the formulation insufficient. Accidental disintegration, which can be caused by an improper manufacturing process or by the GI's unique physiology, including non-disease- dependent factors such as age (pediatrics along with geriatrics), ethnicity, genes, obesity and pregnancy, and gastrointestinal tract (GIT) diseases, all lead to altered drug bioavailability in the colon. Multi-particulate dosing form systems are the most popular formulations because to qualities such as improved bioavailability, decreased toxicity, lower risk of local irritation, and predictable gastrointestinal emptying¹¹.

CDDS has been used to achieve the following objectives12:

1. Sustained administration can minimize dose frequency.
2. Delay medication delivery to reach high concentrations for treating distal gut diseases.
3. Delay in the upper GIT, which is a limiting issue for poorly soluble medicines.
4. Deliver drugs to less metabolically unfriendly regions.
5. This is acid and enzyme labile, similar to proteins.

Benefit of CSDD 13:

1. Targeted medicine delivery.
2. Reduce the dosage to be provided.
3. Reduced side effects.
4. Improved drug usage.
5. It is a prospective place for drugs that are unstable or poorly absorbed in the upper gastrointestinal system.

Advantage 14:

1. Effectively treats inflammatory bowel illnesses such as ulcerative colitis and Crohn's disease.
2. Reduces negative effects in treating colon disorders.
3. Prevents gastrointestinal irritation from NSAIDs.
4. Minimizes first-pass metabolism.
5. Provides a safe environment for proteins and peptides sensitive to stomach fluid and digesting enzymes.
6. Improved patient compliance.
7. Reduced the frequency of administration. As a result, medicine prices are lower.
8. Improves bioavailability by extending retention time for poorly absorbed medicines.

Disadvantages of Colonic Drug Delivery (15-16):

1. Individual pH levels in the small intestine and colon might vary, leading to drug release at unintended CSDDS sites. The pattern of medication release may change from person to person, resulting in unsuccessful treatment.
2. Due to identical pH levels in the small intestine and caecum, formulations may not be site-specific.
3. Colonic drug administration has low site specificity, which is a significant drawback.
4. Diet and illnesses can alter colonic microbiota, affecting medication targeting in the colon. The kind of food in the GIT might influence medication pharmacokinetics. In illness situations, the pH level of the GIT changes from that of healthy volunteers, affecting the targeted release of formulations that release the medicine based on the pH of the intended location.
5. Slow enzyme degradation can disrupt polymer breakdown, affecting medication release profiles.
6. In a time-dependent colonic drug delivery system, significant variations in stomach retention time might result in drug release at the wrong place.
7. Lack of production reproducibility and effectiveness.
8. Need for improved technologies.
9. Excipients are more necessary due to low dosage loading.

Criteria for Selection of Drug for CDDS

CDDS is most suited for medications with low absorption from the stomach or intestine, such as peptides. The medications used to treat inflammatory bowel disease (IBD), ulcerative colitis, diarrhea, and colon cancer are excellent candidates for local colon administration. Drug carrier is another element that impacts CDDS. The choice of carrier for a certain medicine is determined by both the drug's physiochemical characteristics and the condition for which the system is intended. The chemical composition, stability, and partition coefficient of the medicine, as well as the type of absorption enhancer employed, all impact carrier selection. Furthermore, the choice of drug carrier is determined by the drug molecule's functional groups. For example, aniline or nitro groups on a medication can be utilized to form an azo bond with another benzene group. The carriers, which comprise additives such polymers (may be utilized as matrices, hydrogels, or coating agents), may alter the release characteristics and efficacy of the systems.¹⁷.

Need for Colon-Targeted Drug Delivery ^18,19

1. Targeted medication delivery to the colon allows for direct therapy at the illness site, reduced dose, and fewer systemic adverse effects.
2. A site-specific or targeted drug delivery method enables oral administration of peptide and protein medicines. Colon-specific formulations can also be employed to extend medication delivery.
3. The colon can supply both local and systemic drugs for treating inflammatory bowel diseases including ulcerative colitis and Crohn's disease. Such inflammatory disorders are often treated with glucocorticoids and sulphasalazine (targeted).
4. Targeting medications to the colon might improve treatment for other important disorders, such as colorectal cancer.
5. Colonic administration formulations are effective for polar and enzymatically degradable medicines, including therapeutic proteins and peptides, which are heavily influenced by hepatic metabolism.

I. PRIMARY APPROACHES FOR CDDS²⁰

a. pH Sensitive Polymer Coated Drug Delivery to the Colon

The pH of the stomach swings between 1 and 2 during fasting but rises after eating. The proximal small intestine has a pH of around 6.5, whereas the distal small intestine has a pH of about 7.5. From the ileum to the colon, the pH lowers significantly. It is about 6.4 in the cecum. However, pH values as low as 5.7 have been seen in healthy persons' ascending colons. The polymers described as pH dependent in colon-specific drug delivery are insoluble at low pH levels but become more soluble as pH rises. Although a pH-dependent polymer can preserve a formulation in the stomach and proximal small intestine, it may begin to disintegrate in the lower small intestine, resulting in poor site-specificity. The pH fall from the end of the small intestine to the colon can also cause issues, such as long lag periods at the ileocecal junction or fast transit through the ascending colon, which can lead to poor site-specificity in enteric coated single-unit formulations.

b) Delayed or time controlled release drug delivery system

A time-controlled medication delivery system may comprise sustained or delayed release systems. This technique achieves delayed release or colon focused medication delivery by increasing the lag time. The transit time varies by portion of the gastrointestinal system. This transit time is what causes the drug's delayed release. The primary disadvantages of this distribution system are the differences in travel time and food consumption between individuals. It also fluctuates in response to peristalsis, or gastrointestinal contraction.

C) Microbially triggered drug delivery to colon

The colon's micro flora ranges from 1011 to 1012 CFU/ml and is mostly composed of anaerobic bacteria such as bacteroides, bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria, and ruminococcus15.This enormous microflora meets its energy requirements by digesting a variety of substrates that were left undigested in the small intestine, such as di- and trisaccharides, polysaccharides, and so on. The micro flora generates a wide range of enzymes for this fermentation, including glucuronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareductase, deaminase, and urea dehydroxylase.

The enzymes found in the colon are:

1. Reducing enzymes include nitroreductase, azoreductase, N-oxide reductase, sulfoxide reductase, and hydrogenase.

2. Hydrolytic enzymes include esterases, amidases, glycosidase, glucuronidase, and sulfatase.

Because biodegradable enzymes are exclusively found in the colon, using biodegradable polymers for colon-specific medication delivery appears to be a more site-specific strategy than other methods. These polymers protect the medicine from the surroundings of the stomach and small intestine while also allowing it to reach the colon. When they reach the colon, they are absorbed by microorganisms, degraded by enzymes, or broken down by the polymer backbone, resulting in a fall in molecular weight and hence a loss of mechanical strength. They are then unable to retain the medication substance any longer.

A) Prodrug Approach for Drug Delivery to the Colon

At least three criteria should be optimized for site-specific medication delivery utilizing the prodrug method. 1. The prodrug must reach to the targeted site of action as early as possible and uptake from the site must be fast and essentially perfusion rate limited. 2. Once the drug has reached the site, the prodrug must preferentially unleash the active drug in comparison to its conversion at other sites. Once selectively liberated at the site of action, the active drug must be somewhat retained by the tissue.

1. A drug,

2. A targeting moiety,

3. A carrier.

B. Polysaccharide-based Delivery Systems

The use of naturally occurring polysaccharides for medication targeting to the colon is gaining popularity since these monosaccharide polymers are abundant, readily accessible, come in a range of forms with diverse characteristics, and are affordable. They are chemically and biochemically adaptable, safe, very stable, nontoxic, gel-forming, hydrophilic, and biodegradable.

II. NEWLY Developed Approaches for CDDS

a) Pressure-controlled medication delivery devices.

Peristalsis causes larger pressures in the colon than in the small intestine, hence pressure-controlled colon-delivery capsules made of ethyl cellulose, which is insoluble in water, were produced. In such devices, medication release occurs when a water-insoluble polymer capsule disintegrates due to pressure in the colon's lumen. The thickness of the ethyl cellulose membrane is the most essential element determining formulation disintegration. The mechanism also appeared to be dependent on capsule size and density. The colon's luminal material has a greater viscosity than the small intestine due to water reabsorption.

It has been found that medication breakdown in the colon may provide an issue for colon-specific oral drug delivery systems. In pressure-controlled ethyl cellulose single-unit capsules, the medication is liquid. When pressure-controlled capsules were supplied to humans, there were lag periods of three to five hours for medication absorption.

b) Pulsatile colon targeted drug delivery

i) Port system

In this arrangement, the capsule body is enveloped by a semi-permeable membrane. The capsule body is made up of an insoluble plug containing an osmotically active agent and a medication formulation. When the capsule comes into touch with the dissolving fluid, the semi-permeable membrane allows the fluid to flow into the capsule, causing pressure to build up in the capsule body, culminating in drug release owing to the plug being expelled. The medicine is delivered in regular intervals, with a time delay between each period.

ii) Pulsincap system ²¹

In this system the formulation is developed in a capsule form. The plug placed in the capsule controls the release of the drug. Swellable hydrogels are used to seal the drug contents. The capsule gets swelled when it comes in contact with the dissolution fluid and after a lag time the plug gets pushed off from the capsule and the drug will be released. Polymers such as different grades of hydroxyl propyl methyl cellulose (HPMC), poly methyl methacrylate and polyvinyl acetate are used as hydrogel plugs. The lag time is controlled length and point of intersection of the plug in the capsule body.

A various polymers used for designing of the hydrogel plug were various viscosity grades of hydroxyl propyl methyl cellulose, polymethyl methacrylates, poly vinyl acetate and poly ethylene oxide. The length of the plug and its point of insertion into the capsule controlled the lag time. Pulsincap was studied in human volunteers and was reported to be well tolerated. As the swelling hydrogel polymer plug replaced the erodible tablet, the dependence of the dimensional accuracy between the plug and the capsule for the pulling mechanism of the plug from the capsule was also overcome. A release profile is characterized by a period during which no release followed by rapid and complete drug release. Release using this system was found to be reproducible in-vitro and in-vivo. When gastrointestinal transit of the formulations was carried out by gamma scintigraphy, it was found that in six of the eight subjects that the device reached the colon before drug was released. The formulation had been administered with the subjects in a fasting state.

Benefits and Drawbacks of Pulsatile Drug Delivery Systems:

Advantages

• • • Gastric residency duration is predictable, repeatable, and brief.
    • Reduced inter- and intra-subject variability.
    • Improves bioavailability.
    • Improved tolerance and minimized side effects.
    • Reduced chance of local irritation.
    • There is no possibility of dosage dumping.
    • Flexible design.
    • Improve stability.
    • Increase patient comfort and compliance.
    • Create a unique release pattern.
    • Enhance patent protection, globalize products, and outperform competitors.

Drawbacks

• • • Limited manufacturing repeatability and effectiveness.
    • High number of process variables.
    • Multiple formulation processes.
    • Higher production costs.
    • Requires sophisticated technologies.
    • Provided training and skills for manufacturing personnel.

Classification of Pulsatile Drug Delivery Systems.

I. Timed pulsatile release

A. Single-unit system.

B. Multi-Particulate System

II. Stimuli-induced

A. Thermoresponsive Pulsatile Release

B. Chemical stimuli induce pulsatile systems.

III. External stimuli pulsatile release.

A. Electroresponsive Pulsatile Release

B. Magnetically-induced pulsatile release

IV. Pulsatile release systems for vaccine and hormone products

I. TIME CONTROLLED SYSTEM

In this technique, pulsatile discharge occurs after a specific time period to simulate the circadian cycle. Such a pulsatile drug delivery device has two gears: one for instant release and another for pulsed release. These time-controlled systems can be divided into single-unit (e.g., tablet or capsule) or multiple-unit systems.

A. Single Unit System

• • • Capsular Systems.
    • Osmosis-based capsule system.
    • A pulsatile system with an erodible or soluble barrier covering.
    • Pulsatile system with rupturable coatings.

i) Capsular System:

This system's general structure comprises of an insoluble capsule body holding a medicine and a plug that is erodible, swollen, or soluble after a set amount of time.

For example, the Pulsincap system comprises of a water-insoluble capsule body filled with a pharmacological formulation. A swellable hydrogel plug is used to shut the capsule's open end. When the plug comes into touch with GI fluids, it expands and eventually forces its way out of the capsule. This results in medication release as a pulse. The lag time may be adjusted by adjusting the size and position of the plug.

ii) Capsular System Based On Osmosis(Port System):

The Port system was created by Therapeutic system research laboratory in Ann Arbor, Michigan, USA. This technique comprises of a gelatin capsule covered with a semi-permeable membrane (cellulose acetate). The capsule contains an insoluble plug, an osmotically active agent, and a medication formulation. When this cap comes into contact with GI fluids, water diffuses across the semi-permeable membrane, creating increasing pressure within and ejecting the plug after a specified lag time. The lag time is determined by the thickness of the coating. For example, Ritalin (methylphenidate), which is used to treat attention deficit hyperactivity disorder (ADHD) in children, is designed as a PORT system. This approach eliminated second-time dosage, which is favorable to schoolchildren.

iii) Pulsatile System with Erodible or Soluble Barrier Coating:

The majority of pulsatile drug delivery systems consist of reservoir devices covered with a barrier layer. After a certain amount of time, this barrier erodes or dissolves, allowing the medicine to be released quickly. The time lag varies with the thickness of the coating layer. This technique consists of a solid dosage form coated with lipidic barriers incorporating carnauba wax, beeswax, and surfactants (spans). After a lag time proportionate to the thickness of the film, the coat erodes or emulsifies in the aqueous environment, leaving the core open for dispersion.

iv) Pulsatile system based on rupturable coating:

The medication is coated on sugar beads, which are then further coated with an insoluble and swellable top layer. Swelling agents utilized include superdisintegrants such as sodium carboxymethyl cellulose, sodium starch glycollate, and L-hydroxypropyl cellulose. When water is absorbed, the swellable layer swells, causing the film to break and quickly release the medication. The lag time may be changed by altering the coating thickness or adding large volumes of lipophilic plasticizer in the outermost layer.

II. STIMULI BASED PULSATILE RELEASE:

Several polymeric delivery methods undergo phase transitions and exhibit significant swelling-deswelling shifts in response to environmental variables such as solvent composition, ionic strength, temperature, electric fields, and light. Drug release processes include ejection of the drug from the gel as the fluid phase synergizes, drug diffusion along a concentration gradient, electrophoresis of charged drugs towards an oppositely charged electrode, and liberation of the entrapped drug as the gel or micelle complex disintegrate.

1. Thermo-responsive Pulsatile release:

• Temperature Induced System

2. Chemical stimuli induced Pulsatile systems:

• Glucose-responsive insulin release devices
• Inflammation-induced pulsatile release
• Drug release from responding to antibody concentration intelligent gels
• pH sensitive drug delivery system

III. EXTERNAL STIMULI PULSATILE RELEASE:

Externally controlled systems, which are programmed by external stimuli such as magnetic, ultrasound, electrical effect, and irradiation, can also be used to release drugs in a pulsatile manner.

• • • Magnetically induced pulsed release.
    • Electro-responsive pulsatile release.

IV. Pulsatile Release Systems for Vaccine and Hormone Products:

Vaccines are generally given as an initial dose of an antigen, followed by periodic booster shots to establish protective immunity. The frequency of booster doses, and hence the precise immunization regimen, is antigen-specific. Furthermore, co-administration of vaccination adjuvant is frequently necessary to boost the immune response and establish protective immunity. PDDS allow for single-shot vaccinations if the antigen's first booster release can be produced from a single device with controlled booster release time. Vizcarra et al. discovered that in nutritionally anoestrous cows, GnRH delivered in pulses of 2 mg every 5 minutes for 13 days induced a greater frequency of luteal activity by the 13th day than cows given continuous infusions or pulses every 4 hours.

POLYMERS USED IN COLON TARGETING

Polymers are made up of several structural units that are linked together in the same way, forming a chain-like structure. These are nowadays used in formulating various pharmaceutical products. Naturally occurring polymers include gummy exudates, proteins, enzymes, muscle fiber, and polysaccharides. In olden days natural polymers are widely used in pharmacy but a variety of synthetic polymer are used nowadays for pharmaceutical and cosmetic development, using these polymer many therapeutic system of body namely controlled drug delivery systems, are achieved.

1. Natural polymer

Guar gum, Inulin, Pectin, Cyclodextrin, Dextran, Amylase, Chitosan, Chondrotin sulphate, Locust bean gum.

2. Synthetic polymer

Shellac, Ethyl cellulose, Cellulose acetate phthalate, hydroxy propyl methyl cellulose, Eudragit, Poly vinyl acetate phthalate

EVALUATION TEST OF PULSATILE DRUG DELIVERY SYSTEM:²²

Preformulation study: Different physicochemical properties of drug and drug in excipient mass are evaluated in Preformulation study.

Drug excipients interaction study: The Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) techniques can be used to investigate the chemical and physical interactions between the drug and its excipients.

Evaluation of granule:  Angle of repose, Bulk Density, Tapped Density, Carrs Index (or)% Compressibility, and Hausner's Ratio are all measured on the prepared granules.

Tablet Thickness: The thickness of the tablet is measured using a vernier caliper. Five tablets are chosen at random from each formulation and measured in thickness using a vernier caliper scale. The test is performed in triplicate.

Uniformity of weight: Twenty pills are ingested, and their weights are measured individually and collectively using a computerized weighing scale. The average weight of one pill is calculated using the aggregate weight. There are no more than two pills that differ from the average weight by more than twice the percentage stated below.

Hardness/ Crushing strength: Hardness or tablet crushing strength (fc the force required to break a tablet in a diametric compression) is measured using Monsanto Hardness tester. It is expressed in Kg/cm2. Tablets require certain amount of strength or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging, and shipping

Evaluation of polymeric film (only in film coating approach):

a) Visual evaluation: Casted films are visually examined for physical features such as whether they can be readily peeled off the plate, as well as the appearance of the film generated, such as smooth-rough surface, oily-non oily, transparent-opaque.

b) Tensile strength: After drying, the casted films are carefully cut into film strips (40 mm x 20 mm) and tested for tensile strength. The approach used to assess mechanical qualities is based on guidelines. Tensile strength = Breaking.

Force ( F ) / Cross sectional area (A)

c) Folding endurance: The test is performed to determine the effectiveness of the plasticizer and the strength of the film made with varied concentrations of plasticizers. Folding endurance is assessed manually. A strip of film (2 x 2 cm) is cut uniformly and folded repeatedly at the same point until it breaks. The number of times the film could be folded at the same location without breaking is used to calculate folding endurance. The test is performed in triplicate.

d) Mechanical properties: Polymer sheets (6.5 x 6.7 cm2) are attached in a self-designed Teflon holder with numerous holes (10 mm in diameter). Films are fastened with the holder and optionally submerged in 0.1 N HCl at 37°C for 2 hours (wet films). A piercing test with a texture analyzer is used to determine the mechanical characteristics of the dry and wet films (n = 3). A metal probe with a hemispherical end (diameter 5 mm, length 15 cm) is pushed at a speed of 5 mm/min until the film ruptured force-displacement curves are recorded. The following characteristics are calculated:

Puncture strength = Fmax/ ACS

In vitro dissolution study: The in vitro dissolution investigation is carried out utilizing a dissolution test provided in the monograph or standard literature. In typically, dissolving media consist of 900 ml of 0.1 M HCl for 2 hours (since the normal stomach emptying time is 2 hours) and 900 ml of phosphate buffer pH 6.8 for 3 hours (the average small intestine transit time). After 5 hours, the dissolving media is changed with pH 7.4 phosphate buffer (900 ml) and drug release is measured up to a certain hour of dissolution. At specified intervals, a certain volume of dissolving media (1, 2, 5, 10 ml) is extracted, filtered through a 0.45 µm membrane filter, diluted, and analyzed at wavelength maxima using a UV spectrophotometer.

Comparison of dissolution profiles: SUPAC recommendations include a similarity factor (f2) for a modified release dosage form, which is used to compare dissolution characteristics. Dissolution characteristics are thought to be comparable when f2 is between 50 and 100. The dissolving profiles of goods are compared using f2, which is obtained using the following formula: Where n is the dissolution period and Rt and Tt are the reference and test dissolution values at time t.

Kinetic modeling of dissolution data: The dissolution profiles of all batches are fitted to several models, including zero order, first order, Higuchi, Hixon Crowell, Korsmeyer, and Peppas, to determine the kinetics of drug release.

In vivo study of prepared formulation: The produced formulation is evaluated in an in vivo investigation to ensure that the dosage form passes through the GIT. The goal of the in vivo investigation is to determine the capsule's position during its journey through the GI system. In this investigation, medication granules are substituted with barium sulfate. The dosage form is created in the same manner as the optimal formulation. The research involves a volunteer who fasted overnight. The laxative is administered to the participant prior to 12 hours of the trial to thoroughly clear the GIT contents. The X-ray investigation is carried out at 2-, 3-, 5-, and 8-hour intervals.

Pharmacokinetic parameters comparision: Different pharmacokinetic parameters like Cmax (µg/ml), tmax (h), AUC (ng.h/ml), Kel (h-1) and t½ (h) are compare for optimized formulation and marketed tablet.

Anti-inflammatory activity study: Male albino rats weighing between 150 and 180 g are utilized in this investigation; they are kept in four groups of five rats each and have unrestricted access to food and water prior to the procedures.

Group I: Control untreated, received 1% carrageenan only.

Group II: Treated 1% carrageenan injection+ Optimized formulation after 2 hr.

Acute inflammation is generated in rats by injecting 1% carrageenan solution subcutaneously into the subplantar areas of their left hind paws. The thickness of the injected paw is measured immediately after carrageenan injection, as well as after 1, 2, 3, and 4 hours, using a micrometer. The mean % inhibition of edema thickness at each time period is determined from the average rise in thickness in control and treated animals using the equation:

Percentage inhibition in edema thickness = [1 – (Tt/Tc)] X 100

Dissolution–ex vivo permeation study using everted rat intestine: A male Wistar rat's intestine was isolated. A median incision is made in the abdomen to liberate the small intestine, which is then carefully cleaned with a Krebs-Ringer solution. The intestinal tract is everted, and the distal 5 cm portion is used. One end of the isolated everted intestinal segment is attached to a straight cannula, while the other end is threaded to a 1 g weight. The system is filled with Krebs-Ringer solution and fully immersed in the dissolution vessel of the dissolution test device, which holds 900 mL of acceptable dissolving fluidDuring the investigation, assemblies are kept at 37 ± 0.5°C and aerated with a constant supply of bubbling oxygen. Marketed medication samples and an improved batch are examined (n = 3). The medication diffuses from the dissolving medium (mucosalside) to the serosal side (absorption compartment) and is evaluated by a validated analytical technique at regular intervals after filtering via a membrane filter with a pore size of 0.45 µm.

CURRENT SITUATION AND FUTURE SCOPE

Pulsatile medication delivery is becoming increasingly prevalent. The primary advantage of this medication delivery method is that the substance is only delivered when necessary. As a result, the risk of developing drug resistance, which is common in traditional and sustained release formulations, is decreased. Furthermore, several anticancer medications are quite hazardous. These medicines pose serious risks in traditional and sustained release therapy. Currently, various Food and Drug Administration-approved chronotherapeutic medicines are available on the market. This therapy is mostly useful in situations where prolonged activity is not required and medications are harmful. The primary goal of this formulation is to identify circadian rhythms, or relevant indicators, that can trigger the release of medicine from the device.Pulsatile medication delivery is becoming increasingly prevalent. The primary advantage of this medication delivery method is that the substance is only delivered when necessary. As a result, the risk of developing drug resistance, which is common in traditional and sustained release formulations, is decreased. Furthermore, several anticancer medications are quite hazardous. These medicines pose serious risks in traditional and sustained release therapy. Currently, various Food and Drug Administration-approved chronotherapeutic medicines are available on the market. This therapy is mostly useful in situations where prolonged activity is not required and medications are harmful. The primary goal of this formulation is to identify circadian rhythms, or relevant indicators, that can trigger the release of medicine from the device.

CONCLUSION

Colon targeted drug delivery systems are a significant improvement in site-specific drug delivery, providing better therapeutic results in the treatment of colonic diseases. These systems improve medication bioavailability by preserving it from degradation in the upper gastrointestinal tract and selectively releasing it in the colon, decreasing systemic adverse effects. Among the several technologies developed for colon targeting, pulsatile devices such as the Pulsincap technology offer regulated and time-dependent medication release after a predefined lag period.  Use of swellable hydrogel plugs and appropriate polymers allows for fine control of drug release patterns. Despite the benefits, variables such as stomach pH, transit duration, and colonic microbiota may have an impact on the effectiveness of colon-targeted formulations. Continuous research in polymer science, formulation technology, and chronotherapeutic drug delivery is expected to address these constraints. Pulsincap-based systems may play an important role in the future of medication delivery, notably for peptides, proteins, and chronotherapeutic medicines, with enhanced effectiveness and patient compliance.

REFERENCES

1. Philip AK, Philip B. Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Med J. 2010;25(2):79-87. doi: 10.5001/omj.2010.24, PMID 22125706.
2. Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation. Int J Pharm. 2002;235(1-2):1-15. doi: 10.1016/s0378-5173(02)00004-2, PMID 11879735.
3. Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P. Drug delivery systems: an updated review. Int J Pharm Investig. 2012;2(1):2-11. doi: 10.4103/2230-973X.96920, PMID 23071954.
4. Amidon S, Brown JE, Dave VS. Colon-targeted oral drug delivery systems: design trends and approaches. AAPS PharmSciTech. 2015;16(4):731-41. doi: 10.1208/s12249-015-0350-9, PMID 26070545.
5. Nicholas ME, Panaganti S, Prabakaran L, Jayveera K. Novel colon-specific drug delivery system: a review. Int J Pharm Sci Res. 2011;2(10):2545.
6. Hua S. Physiological and pharmaceutical considerations for rectal drug formulations. Front Pharmacol. 2019;10:1196. doi: 10.3389/fphar.2019.01196, PMID 31680970.
7. Chaubey P, Momin M, Sawarkar S. Significance of ligand-anchored polymers for drug targeting in the treatment of colonic disorders. Front Pharmacol. 2019;10:1628. doi: 10.3389/fphar.2019.01628, PMID 32161536.
8. Mehta TJ, Patel A, Patel MR, Patel N. Need of colon specific drug delivery system: review on primary and novel approaches. IJPRD. 2011;3(1):134-53.
9. Wood JD. Normal anatomy, digestion, absorption. Adult short bowel syndrome. Elsevier; 2019. p. 1-16.
10. Stillhart C, Vucicevic K, Augustijns P, Basit AW, Batchelor H, Flanagan TR. Impact of gastrointestinal physiology on drug absorption in special populations-an UNGAP review. Eur J Pharm Sci. 2020;147:105280. doi: 10.1016/j.ejps.2020.105280, PMID 32109493.
11. Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF. The use of formulation technology to assess regional gastrointestinal drug absorption in humans. Eur J Pharm Sci. 2004;21(2-3):179-89. doi: 10.1016/j.ejps.2003.10.003, PMID 14757489.
12. Colon Targeted Drug Delivery-Approach and Future Prospect: A Review Pooja Gupta*1, S. Mukhopadhyay1, Preeti Kothiyal1 Am.J.PharmTechRes.2015;5(4) ISSN:2249-3387.
13. Jain NK: Advances in Controlled and novel Drug Delivery. 1st edition. New Delhi, Cbs publisher and distributors; 2008. p. 86- 90.
14. Sonasaniya Balvir, Dr.M.R.Patel, Dr.K.R.Patel, Dr.N.M.Patel. A Review on colon targeted drug delivery system.International
15. Journal of Universal Pharmacy and Bio Sciences. 2013; 2(1):20-34.
16. VS Mundhe, SS Dodiya. Review article: novel approaches for colon targeted drug delivery. Ind Amer J Pharm Res. 2011; 3: 158-173.
17. P Patel, S Shukla, P Bharadia, V Pandya. Colon targeted drug delivery system- a review. IJUPLS. 2012; 2: 272-291.
18. Vyas SP, Khar RK, Gastroretentive systems. In: Vyas SP, Khar RK, editors. Controlled drug delivery: concepts and advances. New Delhi: Vallabh Prakashan, 2005: 218-253.
19. Mehta TJ et al. Need of colon specific drug delivery system: review on primary and novel approaches. Int J Pharma Res Devel 2011; 3(1): 134- 153.
20. Sandeep Gapat* , Mayuri Gaikwad, Vishwanath Morkhande, S. R. Sayyed, Yadav Vivek, Kure Sapana, A REVIEW ON COLON TARGETED DRUG DELIVERY: AN INNOVATIVE APPROACH, 2015:5(10).
21. Ruchi Joshi, Ashutosh Badola, Preeti Kothiyal, A REVIEW: PULSINCAP A NOVEL DRUG DELIVERY SYSTEM, International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014.
22. Rahath Bushra, Dr.Shahid Mohammed, Dr.A.Shajudha Begum, A REVIEW ON PULSATILE DRUG DELIVERY SYSTEM, 2020 IJRTI | Volume 5, Issue 7 | ISSN: 2456-3315.