SEMINAR ON RECTAL DRUG DELIVERY SYSTEMS

Presented By:Chiranjibi Adhikari1st year M. Pharm. (Pharmaceutics)MALLIGE COLLEGE OF PHARMACY

SEMINAR ONRECTAL DRUG DELIVERY SYSTEMS

INTRODUCTIONRectal drug delivery system is a type of Mucoadhesive drug delivery systems. Such systems involves mucoadhesion , i.e. the attachment of the drug along with a suitable carrier to the mucous membrane.The rectal route though rarely the first choice of drug administration, serves as an alternative to oral and invasive administration. Rectal drug delivery is so pivotal when the oral medication is not possible, intra venous access is not possible and when the patients have difficulty in swallowing, nausea and vomiting. For a long period of time the rectal route was used only for the administration of local anesthetics, anti-hemorrhoidal, vermifugal, anti-bacterial and laxative agents. Now the majority of drugs are formulated in the rectal dosage form to produce a systemic effect.

Advantages of Rectal drug delivery systemIrritation to the stomach and small intestine associated with certain drugs can be avoided. E.g.- NSAIDs: Aspirin, Ibuprofen, Naproxen.Absorption enhancement of many low molecular weight drugs, proteins and peptides. Contact with digestive fluid is avoided, thereby preventing acidic and enzymatic degradation of some drug. E.g. - Protein peptide drug delivery by rectal offers low levels of protease activity particularly of pancreatic origin.Hepatic first pass elimination of high clearance drug may be partially avoided. E.g. - Lidocaine, Proponalol, Morphine, etc.Possibility of rate controlled rectal drug delivery with Hydrogel preparation. E.g. - Antipyrine and Theophylline.

6. Rectal drug delivery is useful in pediatric, geriatric and unconscious patient specially having difficulty in swallowing oral medicine. 7. When oral intake is restricted such as prior to x- ray studies, before surgery or in patient having diseases of upper GIT.8. Drug delivery can be stopped by removing the dosage form and drug absorption can be easily interrupted in cases of accidental overdose or suicide attempts.9. Drug which traditionally is only given parentally may be administered rectally. E.g. - Peptides and other hydrophilic drugs.10. Retention of large volumes. Eg. 300 ml of Lactulose solution is given via enema for the treatment of hepatic encephalopathy.

Applications of Rectal DDS1. Rectal administration of the anti epileptic drugsFirst pass metabolism of anti epileptic drugs can be partially avoided.Diazepam solution administered rectally result in rapid and complete absorption with peak plasma concentration attained within 5-15 min. The rectal formulation of carbamazepin, lamotrigine, levetiracetam, phenobarbital, topiramate and valproate have been found to be bioequivalent to oral tablets and oral suspension.2. Analgesics by rectal routeControlled release morphine suppositories are observed to greater extent (larger AUC) than oral controlled release tablets. The analgesia can be maintained without any side effects.Similar observations were found with opioids (oxycodone and methacodoen) and NSAIDs (raproxem, diclofenac and ibuprofen).

Disadvantages of Rectal ddsMany drugs are poorly or erratically absorbed across the rectal mucosa.Dissolution problems due to the small fluid content of the rectum.Drug metabolism by micro organisms and rectal mucosa.They are inconvenient and not preferred by patients. Frequently unpredictable because of leak or expulsion after insertion.

Table 1: Category of Suppositories Indication and adverse effects

ANATOMY AND PHYSIOLOGY OF RECTUMThe rectum is a hollow organ that comprises of the last portion of the large intestine and extends 12 -18cm distally. The rectal wall is formed by an epithelium which is one cell layer thick and composed of cylindrical cells and goblet cells which secret mucus. The surface area available for drug absorption in the rectum is approximately 200- 400cm. Volume of fluid in the rectum is about 1-3ml and is viscous. The rectal milieu is constant as its pH is 7.5-8.The superior rectal vein which peruses the upper part of the rectum drains into the portal vein and subsequently into the liver where as the middle and inferior rectal veins drains the lower part of the rectum and enter into the inferior vena cava and bypass the liver before entering the general circulation.

Fig: Vasculature of human rectum

ABSORPTION OF DRUGS IN RECTUMAbsorption of drugs from rectal epithelium involves two transport routes:transcellular route & paracellular route. An uptake mechanism in transcellular route depends on lipophilicity where paracellular route is drug diffusion through a space between epitelial cells. Aqueous and alcoholic solutions are absorbed quickly where as suspensions and suppositories exhibit slow & continuous absorption. Alkaline solutions are quickly absorbed than acid solutions. Methods for improving rectal absorption of the drugs include:-Modification of the barrier functions of the mucosal membrane.Chemical modification of drug to increase partition co efficient. Formulation modification to improve dissolution step of poorly aqueous soluble drugs.

Factors affecting the absorption of drug from rectum1. Physiological factors- Colonic content- Drug will have greater opportunity to get absorbed when the rectum is empty. Circulation route- If the drug is absorbed from lower hamorrhoidal veins it will directly take the drug to inferior venacava.pH of rectal fluids- weaker acids and bases are more readily absorbed than the stronger, highly ionized ones. 2. Physiochemical factors- Lipid-water partition coefficient- Water-soluble, oil-insoluble salts are preferred in fat-based suppositories. Degree of ionization- unionized drugs are highly absorbed.Particle size - The smaller the particle, greater the absorption.Nature of base - If the base interacts with the drug or if it irritates the mucus membrane, it will decrease the absorption.

ABSORPTION ENHANCERSEnamine derivatives- Absorption of Amino acid in aqueous solution with ethylacetoacetate increases with an increase in the pH.Salicylates and its derivatives promots rectal absorption of hydrophilic antibiotics and polypeptides.Fatty acids- Medium chain length fatty acids are absorption promoting adjuvants for ampicillin and hydrophilic antibiotics.Strong chelating agents- EDTA increases the transport of both antipyrine (smaller mol. Wt.) and phenol red( larger mol. Wt.).Protease inhibitors- e.g. aprotinin, trypsin, bacitracin, puromycin, bestatin and bile salts such as Na-GC. Chemical modification- e.g. Acyl derivatives of insulinCyclodextrins- Enhance rectal absorption of lipophilic drugs and inabsorbable drugs such as antibiotics, proteins and peptides .

Table 2: Uses of Cyclodextrins in rectal delivery of drugs

DIFFERENT TYPES OF RECTAL DOSAGE FORMSRectal semisolids: Creams, Gels, Ointments and SuppositoriesRectal liquids : Solutions and Suspensions Rectal aerosolsRectal cream, gels and ointments- They are largely used for topical application to treat local conditions of anorectal pruritis, inflammation and the pain and discomfort associated with hemorrhoids. The drugs include: astringents (eg. Zinc oxide), local anaestheics (eg. Pramoxine HCL), protectants and lubricants ( eg. Cocoa butter, lanolin) and antipruritis and anti inflammatory agents ( eg. Hydrocortisone).

The bases used in anorectal creams and ointments includes combinations of polyethylene glycol 300 & 3350 , emulsion cream bases using cetyl alcohol & cetyl esters wax , white petroleum and mineral oil. The preservatives like methylparaben, propylparaben, benzlyacohol and butylated hydrocortisole (BHA) are also used. Rectal ointments creams and gels are packed with special perforated plastic tips for products to be administered in to the anus.

Fig: rectal cream and ointment applicators

The use of gels, foams or ointments for rectal administration can afford advantages over liquid formulations because retention of the dosage form in the rectal cavity reduces patient compliance problems.Drug release and subsequent pharmacologic action is usually faster with semisolid formulations than with solid suppositories since a lag time is not required for melting or dissolution.Several commercial products includes Diastat Gel (Diazepam), Analpram HC cream (hydrocortisone acetate + pramoxine HCL) , ANUSOL ointment (starch), Pilex Ointment, etc.

RECTAL SUPPOSITORIESTypically, rectal suppositories these are torpedo-shaped solid dosage forms composed of fatty bases (low-melting) or water-soluble bases (dissolving) which vary in weight from 1 g (children) to 2.5 g (adult). Suppository base composition plays an important role in both the rate and extent of release of medications. Lipophilic drugs are usually incorporated into water-soluble bases while hydrophilic drugs are formulated into the fatty base suppositories. For suppositories made from fatty bases, melting should occur rapidly near body temperature (37C). Ideally the resultant melt would readily flow to provide thin, broad coverage of the rectal tissue, thereby minimizing lag time effects due to slow release of the drug from the suppository base. Water-soluble suppositories should likewise readily dissolve at 37C to facilitate drug release and absorption.

The ideal suppository base should be nontoxic, nonirritating, inert, compatible with medicaments, and easily formed by compression or molding. It should also dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. Table 3: Suppository bases

Suppositories are suited particularly for producing local action but may also be used to produce a systemic effect or to exert a mechanical effect to facilitate emptying lower bowel. The suppository may be useful as a sustained release formulation for the treatment of chronic diseases like essential hypertension, asthma, diabetes, AIDS, anemia, etc. HPMC and Glyceryl Behenate polymer in higher concentration are used to formulate sustained release suppositories.

Methods of Preparation of suppositoriesI) Hand RollingIt is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a base. It has the advantage of avoiding the necessity of heating the cocoa butter. The base is first grated and then kneaded with active ingredients by the use of mortar and pestle until the mass is plastic. The mass is formed into a ball in the palm of the hands, and then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape. Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded & softened.

II) Compression MoldingIt is a method of preparing uniform and elegant suppositories from a mixed mass of cold-grated suppository base and medicaments. A hand turned wheel pushes a piston against the suppository mass contained in a cylinder, so that the mass is forced into compressed mold. This method avoids the possibilities of sedimentation of the insoluble solids in the suppository base. The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base based on the density factors of the active ingredients.Air entrapment is the major disadvantage.

III) Fusion/ Pour MoldingIt involves first melting the suppository base and then emulsifying or suspending the drug in the melted base. The mixture is removed from the heat and poured into cooled metal molds, which are usually chrome- or nickel-plated. When the mixture has congealed, the suppositories are removed from the mold. When they are mixed, melted and poured into suppository mold cavities, they occupy a volume the volume of the mold cavity. Since the components are measured by weight but compounded by volume, density calculations and mold calibrations are required to provide accurate doses.The fusion method can be used with all types of suppositories and must be used with most of them. Suppositories can be produced for both small and Large scale.

New Approach- Double Casting Technique

Packaging of suppository is done after lubrication with proper lubricant in aluminum foil or in other suitable material and with indication [STORE IN A COOL PLACE].Several commercial suppository products include- ANUSOL HC ( Hydrocortisone ), DULCOLAX ( Bisacodyl ) , CANASA (Mesalamine ) , NUMORPHAN ( Oxymorphane ), PANADOL ( Paracetamol ), etc.

Acetaminophen Glycero-Gelatin Laxative Eucalyptol Anucort-HC Fig: Different types of suppositories

RECTAL LIQUIDS: Rectal Solutions, suspensions, or retention enemas represent rectal dosage forms with very limited application, largely due to inconvenience of use and poor patient compliance. In many cases, these formulations are utilized to administer contrast media and imaging agents for lower GI roentgenography. It involves injecting a liquid, typically a laxative, with a syringe into the rectum. The medicament is incorporated into a base such as cocoa butter which melts at body temperature, or into one such as glycerinated gelatin or PEG which slowly dissolves in the mucous secretions. Retention enema: The drugs like hydrocortisone (local effect) or aminophylline (systemic effect) etc are used in this dosage form. Evacuation enema: It is used for cleansing of bowel. The agents are sodium phosphate and sodium biphosphate, glycerin and doccusate potassium and light mineral oil.

Fig: Rectal liquid inserts (Bubble insert) Fig: Liquid applicator (squeeze insert)

RECTAL AEROSOLS: Rectal aerosols or foams products are accompanied by applicators to facilitate administration. The applicator is attached to the container and filled with a measured dose of product. Metered dose aerosols are available. The inserter is inserted in to the anus and the plunger is pushed to deliver the drug product.Several marketed rectal aerosols are like PROCTOFOAM HC (Pramoxine), CORTIFOAM (Hydrocortisone), etc.

Evaluation of Suppositories

1. Weight VariationAll the suppositories are weighed and average weight is calculated.No suppositories should deviate from average weight by > 5% except two, which may deviate not > 7.5 %.

2. Disintegration TestThe disintegration test is performed on six suppositories using tablet disintegration test apparatus. 160ml of distilled water is used as medium at 37C.The time required for complete disintegration of suppository is determined.

3. Breaking Test- It is designed as a method for measuring the fragility or brittleness.Water at 37C is pumped through the double wall chamber of the apparatus. The test suppository is placed in the dry inner chamber, which supports a disc to which a rod is attached. The other end of the rod consists of another disc to which weights are applied. The test is conducted by placing 600 g on the platform. At 1 min intervals, 200 g weights are added, and the weight at which the suppository collapses is the breaking point. The desired breakpoints of various shaped suppositories are established as the level that withstands the break forces caused by production, packing, shipping and patient in-use handling.

4. Macro Melting Range TestFor macro melting range test, the formulation is filled to about 1cm height in capillary tubes of 10 cm length and dipped in a beaker containing water. The temperature is raised slowly and the temperature at which the mass liquefies is recorded.

5. Drug ContentFor determination of drug content the suppositories are dissolved in suitable solvent. After the solution is filtered; and the filtrate is diluted suitably, the absorbance is measured against blank at particular nm using UV Spectrophotometer.

6. Liquefaction Time & TemperatureLiquefaction/ softening time and temperature can be estimated using fabricated instrument. A big pipette is taken having a narrow opening on one side and broad opening on another side. The pipette is dipped in hot water maintained at 37 C so that narrow end faces toward hot water. The sample suppository is introduced from the top of the pipette through broad end and carefully pushed down its length until it reaches narrow end. A glass rod is then inserted so that it rests over the suppository. The temperature at which the glass rods just come down is noted that represents the liquefaction temperature. The time at which glass rod reaches to narrow end after complete melting of suppositories represents the liquefaction time.

7. Dissolution TestIn vitro dissolution studies of suppositories are carried out in tablet dissolution test apparatus employing a wire mess basket, or a membrane to separate the sample chamber from the reservoir. One suppository is used in each test at specified rpm using buffer at 370.5C as dissolution medium. At predetermined time intervals 5 ml sample are withdrawn by means of syringe fitted with a pre filter then filtered through watman filter paper. The volume withdrawn at each interval is replaced with same quantity of fresh dissolution medium and maintained at 370.5C. The sample is analyzed for drug release by measuring the absorbance at particular nm using UV visible spectrophotometer after suitable withdrawn sample. Cumulative percent of drug released is calculated and plotted against time.

CONCLUSIONRectal administration is truly explored as a potential drug delivery system particularly for drugs that are either too irritating for the gut or undergo extensive first pass metabolism. The rectal drug delivery system offer patients an option that is less invasive and the drug can be administered in unconscious and pediatric patients.Rectal drug delivery with the advantages of enhancement in drug absorption with enhancers, and its usefulness as a Sustained-release formulation for the long-term treatment of chronic diseases will undoubtedly be a pioneer in formulation of various challenging compounds.

REFERENCES

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