Topical and Rectal absorption of drugs, formulation and evaluation.pptx

Pharmaceutics, Pharmaceutical technology, Industrial Pharmacy - B.Pharma and M. Pharma

1. Topical and Rectal absorption of drugs, formulation and evaluation Department of Pharmaceutical science Dr. Harisingh Gour Vishwavidyalaya, Sagar M.P. Prepared by: Name - Amit Sahu Roll No. – Y21254005 M. Pharma 1 st Sem. Submitted to: Prof. Sanjay K. Jain Dr. Dharmendra Jain

2. Topical drug delivery The application of a formulation to the skin to treat a local disorder, i.e. the active pharmaceutical ingredient acts within the skin or at the underlying tissue. Introductions

3. Structure of the skin 1. Epidermis The epidermis is approximately 50 - 150μm thick and consists largely of constantly renewing, outward moving cells called keratinocytes .

4. The outermost layer of the epidermis is the stratum corneum or horny layer , which consists of compacted, dead, keratinized cells in stratified layers with a density of 1.55 . The stratum corneum is the rate-limiting barrier that restricts the inward and outward movement of chemical substances. 2. Dermis A layer typically 3 mm to 5 mm thick that is the major component of human skin. The dermis is composed of a network of mainly collagen and elastin in a mucopolysaccharide gel ; essentially this combination provides an aqueous environment .

5. Contained and supported within the dermis are numerous blood vessels , lymphatics , and nerves , as well as the epidermal appendages such as the hair follicles , sebaceous glands , and sweat glands . 3. Hypodermis The dermis rests on the hypodermis (subcutis) which is composed of loose fatty connective tissue. Its thickness varies considerably over the surface of the body as well as between individuals.

6. Percutaneous Absorption Drug dissolution in vehicles Drug diffusion through vehicle to skin Trans follicular route Trans epidermal route Partitioning into sebaceous gland Partitioning into stratum corneum Partitioning into viable epidermis Diffusion through viable epidermis Diffusion through upper dermis Systemic circulation

7. Factors affecting Percutaneous absorption of drugs: Solubility and partition co- efficient pH condition Penetrant concentration 1. Physicochemical properties of permeant molecule 2. Physiological and pathological condition of skin Lipid film Skin hydration Skin temperature

8. 3. Biological factors Effect of vehicle Pathological injury to skin Skin age Thickness of Stratum Corneum Skin condition Chronic use of certain drugs Presence of hair follicles Blood flow Regional skin sites Species difference

9. Topical formulations Liquid preparations Ointments Gels (jellies) Creams Pastes 2. Semisolid Preparations 3. Aerosols Lotion Liniment Collidines 2. Solid Preparations Powders

10. Formulation consideration 1. Drug Selection The ideal properties of a molecule penetrating stratum corneum: Low molecular mass, preferably less than 600 Da. Adequate solubility in oil and water. High but balanced (optimal) partition coefficient. Low melting point. Insoluble drugs must be uniformly dispersed throughout the vehicle to ensure homogeneity of the product.

11. 2. Vehicles/Semisolid Bases: The USP recognizes four classes of semisolid bases under the general classification of ointment I. Oleaginous Bases Hydrocarbons Petrolatum (soft paraffin) Mineral oil (liquid paraffin) Hydrocarbon waxes (hard paraffin) Vegetable oils Peanut Oil, Almond Oil, Sesame Oil, Olive Oil Oily silicones Dimethicone and Cyclomethicone

12. II. Absorption Bases These bases are usually anhydrous and they do absorb aqueous solutions, these are two types Anhydrous absorption bases: Hydrous absorption bases: These are w/o emulsions with ability to absorb additional water. Eg. Hydrous lanolin They absorb water to form water-in-oil emulsions. Eg. Anhydrous lanolin (wool fat), beeswax, hydrophilic petrolatum and organosilicones

13. III. Water-removable Bases: The water-removable bases are oil-in-water emulsions and are referred to as “creams.” The vanishing cream bases fall into this category. The vanishing creams are so termed because upon application and rubbing into the skin, there is little or no visible evidence of their former presence. IV. Water-soluble Bases: Water-soluble vehicles are prepared from mixtures of high- and low molecular-weight polyethylene glycols or macrogol, which have the general formula: HOCH 2 [CH 2 OCH 2 ]n CH 2 OH.

14. 3. Penetration Enhancers: Materials which increase the rate of absorption of topically applied drugs. These agents are often called “accelerants” or “sorption promoters” or “penetration enhancers”. Penetration enhancers Examples Mechanism of action Sulphoxides Dimethyl sulfoxide Dimethylacetamide Dimethylformamide Skin damage, Denature proteins, Convert keratin conformation from  -helical to  -sheet, lipid fluidization Decylmethylsulfoxide

15. Pyrrolidones N-methyl-2-pyrroli done 2 pyrrolidone Alter solvent nature of membrane, generate reservoir within skin Fatty acids Oleic acid, Lauric acid, Linoleic acid, Linolenic Interact and modify SC lipid bilayers, Lipid fluidization Alcohols, glycols Ethanol, Octanol, Propylene glycol, Transcutol Increase drug solubility and thermodynamic activity, extract lipids from SC, Surfactants Sodium lauryl sulphate, Cetrimide Increase transepidermal water loss, changes membrane permeability

16. 4. Emulsifiers : The water-soluble soaps were among the first emulsifiers used for semisolid oil-in-water emulsions. The viscosity of the cream or ointment prevents coalescence of the emulsified phases and helps to stabilize the emulsion. The addition of fatty polar substances, such as cetyl alcohol and glyceryl monostearate , tends to stabilize the semisolid oil-in-water emulsion. 5. Humectants : Glycerine , propylene glycol, sorbitol 70%, and the lower molecular weight polyethylene glycols are used as humectants in creams.

17. 6. Preservatives: The preservatives are added to semisolids to prevent contamination, deterioration, and spoilage by bacteria and fungi, since many of the components in these preparations serve as substrates for these microorganisms. Methylparabens and propylparabens, Quaternary ammonium compounds (e.g. benzalkonium chloride) or the phenylmercuric salts. Boric acid may be used in the ophthalmic preparations.

18. 7. Antioxidants: Antioxidants are added to semisolids whenever oxidative deterioration is anticipated. Commercial used antioxidants are Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate.

19. Evaluations: 1. Extrudability and spreadability : Ease with which semisolid come out from tube or pack and ease with which it spreads over skin is designated as extrudability and spreadability , respectively. Force required, making the ointment move out or extrude through uncapped tube, placed below the plunger is test of extrudability.

20. In spreadability test, a small quantity of ointment is placed between two slides one of which is movable. Force is applied to movable slide and the corresponding distance traveled is recorded. Graphical plots between applied force and distance traveled indicate spreadability .

21. 2. In vitro diffusion study: Franz diffusion cell was used for the drug release studies. Ointment was evenly applied onto the surface of cellulose membrane. The cellulose membrane was clamped between the donor and the receptor chamber of diffusion cell. A. Diffusion method

22. The receptor compartment was filled with phosphate buffer pH 7.4, and the assembly was maintained at 37°C ± 0.5 under constant magnetic stirring. 300 mg of ointment was applied to the membrane on the donor compartment and then covered with aluminum foil to prevent drying out. Aliquots were withdrawn at predetermined time intervals over a period of 1h and amount of drug released was analyzed by using UV spectrophotometer. B. Agar cup plate method: This method is generally based on diffusion pattern of base and which drug transfer spontaneously from region of higher concentration to lower concentration.

23. Make a hole at the center of agar plate with the help of hollow glass rod and fill the ointment formulations. Plates are keep aside to determine the releasing property by measuring the radius (or) diameter of colored zone at ½,1,1½, 2, 2½, and 3 hours time intervals.

24. 3. Ex vivo permeation study: The prepared rat skin was mounted on the Franz diffusion cell (with effective diffusion area 3.14 cm2 and 7 ml cell volume) with stratum corneum facing upward. The receptor compartment was filled with phosphate buffer pH 7.4, and the assembly was maintained at 37°C±0.5 under constant magnetic stirring. The amount of drug permeated through rat skin was carried out as per method described in diffusion study.

25. 4. Irritation test: Allergy or irritation due to a specific ointment base component is more frequent and more important, hence a number of test procedures have been devised to test irritancy level of an ointment formulation. Irritation potential of formulation is evaluated In vitro—HET CAM test on eggs, In vivo—Draize dermal irritation test on rabbits and In humans—Draize- Shelanski Repeat Insult Patch Test.

26. Rectal drug delivery The rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. This includes the local treatment of constipation, hemorrhoids, anal fissures, inflammation, and hyperkalemia. Rectal formulations for systemic drug delivery are used clinically for the treatment of pain, fever, nausea and vomiting, migraines, allergies, and sedation.

27. The reasons for choosing the rectal route for systemic drug administration: The patient is unable to swallow. This is the case with unconscious patients , preoperatively and postoperatively , patients with gastrointestinal tract problems , very young or very old patients , and patients with certain central nervous system (CNS) disorders, such as epilepsy . The drug under consideration is not well suited for oral administration; for example, drugs causing gastrointestinal side effects , unpalatable drugs and those which are susceptible to extensive first-pass metabolism and enzymatic degradation in the gastrointestinal tract.

28. Absorption of drugs from the rectum: Insertion of the dosage form into the rectum Suspended drugs leave the vehicle Dissolve in the rectal fluid Dissolved drug molecules will diffuse through the rectal mucus Then into the epithelium of the rectal wall membrane by the passive diffusion process.

29. Factors affecting the absorption of drug from rectum: 1) Physiological factors of drug: Colonic content - Drug will have greater opportunity to get absorbed when the rectum is empty. For this purpose enema is given before rectal drug administration. Circulation route – If the drug is absorbed from lower hamorrhoidal veins it will directly take the drug to inferior venacava, so the absorption will be rapid and effective. pH and lack of buffering capacity of rectal fluids - The rectal fluid have pH 7-8, hence no effective buffering capacity. So ionized or un-ionized form of the drugs will be having marked influence.

30. 2) Physicochemical factors of drug: Lipid-water solubility – A lipophilic drug if given with fatty bases it will not escape from base easily. So absorption is altered. Particle size – The smaller the particle the greater will be the solubility. Nature of base- If the base interacts with the drug or if it irritates the mucus membrane it will decrease the absorption. Mainly in case of suppositories .  

31. Rectal semisolids: 1) Creams 2) Gels 3) Ointments 4) Suppositories Rectal liquids: 1) Solutions 2) Suspensions Rectal aerosols Different types of rectal dosage forms:

32. Rectal semisolids: Rectal cream, gels and ointments These preparations are used for topical application to the perianal area for insertion within the anal canal. They largely are used to treat inflammation, the pain and discomfort. The drugs includes astringents ( eg. Zinc oxide ), protectants and lubricants ( eg. Cocoa butter, lanolin ), local anaestheics ( eg. Lidocaine HCL ), 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 , and white petroleum and mineral oil .

33. The preservatives like methylparaben, propylparaben, benzylalcohol and Antioxidant butylated hydroxyanisole (BHA) are also used. Several commercial rectal creams and ointments and gels: RECTOGESIC ointment - Glyceryl trinitrate ANOBLISS Cream - Lidocaine + Nifedipine ANALPRAM - HC cream - Pramoxine + Hydrocortisone DIASTAT Gel - Diazepam

34. APPLICATION - Before applying rectal ointments and cream the perianal skin and the affected area should be cleaned and dried. Special types of applicators are used for applications of creams & several market preparations are available with perforated applicator tips and inserters. Fig. Rectal cream and ointment applicator Fig. Rectal gel inserter

35. suppositories: These are generally intended for use in the rectum, vagina, and to a lesser extent, the urethra for local or systemic effects. Rectal suppositories Typically, these are torpedo-shaped dosage forms, usually employ vehicles that melt or soften at body temperature . Vary in weight from 1 g (children) to 2.5 g (adult). Suppositories are ovoid or conical medicated solids intended for insertion into one of the several orifices of the body, excluding the mouth. This term derives from the Latin suppositus , meaning “ to place under .”

36. SUPPOSITORY BASES: The Ideal Suppository Base :- The majority of components melt at rectal temperature 36°C. The base is completely nontoxic and nonirritating. It is compatible with a broad variety of drugs. It has no metastable forms. It shrinks sufficiently on cooling to release itself from the mold without the need for mold lubricants. It is nonsensitizing . It has wetting and emulsifying properties.

37. It is stable on storage, i.e. does not change color, odor, or drug release pattern. It can be manufactured by molding by either hand, machine, compression, or extrusion. Oleaginous base Aqueous base Emulsifying base Suppository Base

38. Oleaginous base: Cocoa butter is the most widely used suppository base. It satisfies many of the requirements for an ideal base. Cocoa butter is primarily a triglyceride, yellowish-white, solid, brittle fat, which smells and tastes like chocolate. Its melting point lies between 30°C and 35°C. Oleaginous base Glycerogelatin : It is a mixture of glycerin , water and gelatin . Soap glycerin: In this case, soap is employed instead of glycerin for hardening. PEG bases: Postonals , Carbowaxes and Macrogols.

39. Emulsifying base These are synthetic bases and a number of proprietary synthetic bases are available in the market. Eg. Witepsol , Massa estarinum , Massuppol

40. MANUFACTURE OF SUPPOSITORIES: Hand Molding: The simplest and oldest method of preparing a suppository is by hand. The base is first grated and then kneaded with the active ingredients by use of a mortar and pestle, until the resultant mass is plastic and thoroughly blended. The mass is then rolled into a cylindric rod of desired length and diameter, of the intended weight. Starch or talcum powder on the rolling surface and hands prevent the mass from adhering.

41. Compression Molding: The cold compression method is simple and results in a more elegant appearance than does hand molding. It avoids the possibilities of sedimentation of the insoluble solids in the suppository base, but is too slow for large-scale production.

42. Pour Molding: The most commonly used method for producing suppositories on both a small and a large scale is the molding process. First, the base material is melted and then the active ingredients are either emulsified or suspended in it. Finally, the mass is poured into cooled metal molds, which are usually chrome-or nickel-plated.

43. Lubrication of mould : Sr. No. Base Lubricants 1. Cocoa butter Soft soap, Glycerin , Alcohol 90% 2. Glycero-gelatin Liquid paraffin or Arachis oil 3. Emulsifying base No lubricant is used. Dosage Replacement Factor / Displacement value: The amount of base that is replaced by active ingredients in the suppository formulation can be calculated. The replacement factor, f, is derived from the following equation:   Where, E is weight of pure base suppositories, G is weight of suppositories with X% active ingredient.

44. EVALUATION OF SUPPOSITORIES Weight Variation Weight variation test is run by weighing suppositories individually calculating the average weights and comparing the individual tablet weights to the average. The value of weight variation test is expressed in percentage. The following formula is used:   No suppositories should deviate from average weight by more than 5%.

45. Hardness (fracture point) Hardness test or fracture point test is determine the tensile strength of the suppositories to access whether they will be able to withstand the hazards of packing and transporting. Hardness test of the suppositories done by using Monsanto hardness tester. The weight required for suppository to collapse will considerd as hardness of the suppository.

46. Macro Melting Range Test Measure of the time it takes for the entire suppository to melt when immersed in a constant temperature (37°C) water bath. In contrast, the micromelting range test is the melting range measured in capillary tubes for the fat base only. The suppository melting point apparatus by ERWEKA® consists of a graduated tube like glass test chamber. The sample to be tested is placed in a spiral shaped glass test basket inside the test chamber which itself is surrounded by a water jacket heated by circulation thermostat. The time for the entire suppository to melt or disperse in the surrounding water is measured.

47. Softening Time Tests Softening time test apparatus consists of a U-tube partially submersed in a constant-temperature water bath. A constriction on one side holds the suppository in place in the tube. A glass rod is placed on top of the suppository, and the time for the rod to pass through to the constriction is recorded as the “softening time”. BreakingTests The breaking test is designed as a method for measuring the fragility or brittleness of suppositories.

48. The apparatus used for the test consists of a double-wall chamber in which the test suppository is placed. Water at 37°C is pumped through the double walls of the chamber, and the suppository, contained in the dry inner chamber, 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

49. References: Aulton M. E., Taylor K. M., “ Aulton’s Pharmaceutics The Design and Manufacture of Medicines”, 5th edition, Elsevier publications New York, 2018, page no. 715-737, 740-749. Gennaro A. R., Remington: “The Science and Practice of Pharmacy”, 20th edition, volume – I, Lippincott Williams & Wilkins publications, Philadelphia,2001, page no. 836-850, 855. Lachman L., Liberman H. A., Kanig , J. L., “The Theory and Practice of Industrial Pharmacy”, 3rd edition, Varghesh publishing house Bombay, 1991, page no. 534-562. MARU A.D., LAHOTI S.R., "Formulation and Evaluation of Ointment Containing Sunflower Wax", Asian Journal of Pharmaceutical and Clinical Reserch , 2019.

50. Rao V., Reshma D., Padmalatha , "Invitro Evaluation of Salicylic Acid Release from an Ointment and Cream By Agar Plate Method", World Journal Of Pharmacy And Pharmaceutical Sciences, 2014. Zuikina Y., Polovko N., Strilets O., Strelnikov L.,"The in vitro Release Testing and The Antimicrobial Activity of Semi-solid Dosage forms which contain Salicylic acid", Farmacia , 2021. Gupta A. , Mishra A. K., Singh A. K. , Gupta V., Bansal P., “ Formulation and evaluation of topical gel of diclofenac sodium using different polymers”, Drug Invention Today Vol.2.Issue 5.May 2010 Baviskar P, Jaiswal S, Sadique S, Landged A. Formulation and evaluation of lornoxicam suppositories. The Pharma Innovation. 2013 Sep 1;2(7, Part A):20.