semisolids

1. semisolids Lecturer: dr. Asmaa abdelaziz Mohamed Faculty of pharamcay Ibn hayan University 1

2. semisolid Dosage Forms • Ointments, creams, and gels are semisolid dosage forms intended for topical application. • They is applied to the skin, the surface of the eye, nasally, vaginally, or rectally. • Most of these preparations are used for the effects of the therapeutic agents they contain. The unmedicated ones are used for their physical effects as protectants, emollients or lubricants. • Topical preparations are used for both local and systemic effects. A transdermal product delivers drugs through the skin (percutaneous absorption) to the general circulation for systemic effects. 2

3. Ointments are one of the most commonly used semisolids. They compose of active ingredient and ointment base. Ointment Bases Ointment bases are generally classified into four groups: a)Oleoginous Bases b)Absorption Bases c)Water-Removable Bases d)Water-Soluble Bases 3

4. Oint bases a)Oleaginous Bases (hydrocarbon bases): • On application to the skin, they have an emollient effect and protect against the escape of moisture. They can remain on the skin for long periods without drying, and because of their immiscibility with water are difficult to wash off. Water and aqueous preparations may be incorporated, but only in small amounts and with some difficulty. Such as Petrolatum (Vaseline). • When powdered substances are to be added into hydrocarbon bases, liquid petrolatum (mineral oil) used as levigating agent. 4

5. b)Absorption Bases (emulsion bases) • permit the incorporation of aqueous solutions resulting in the formation of W/O emulsions. They have the capacity to absorb water up to three times their weight. • They not easily removed from the skin by washing, because the external phase of the emulsion is oleaginous. • Absorption bases are useful to incorporate small volumes of aqueous solutions and are used mostly in the preparation of ophthalmic ointments. 5

6. c)Water-Removable Bases • are O/W emulsions resembling creams. Because the external phase of the emulsion is aqueous, they are easily washed from skin. • They may be diluted with water or aqueous solutions. 6

7. d) Water-Soluble Bases • do not contain oleaginous part (greaseless),completely water washable. • Because they soften with the addition of water, large amounts of aqueous solutions cannot be incorporated into these bases. • They mostly are used for incorporation of solid substances. • Polyethylene glycol is a water-soluble base. • PEGs having molecular weight below 600 are clear, colorless liquids; those with molecular weight above 1,000 are waxy solid materials; and those with molecular weight in between are semisolids and used in ointments.

8. Selection of the Appropriate Base depends on a number of factors such as: • Desired release rate of the drug from the ointment base. • Desirability of topical or percutaneous drug absorption. • Desirability of occlusion of moisture from the skin. • Stability of the drug in the ointment base. • Effect of the drug on the consistency or other features of the ointment base. • Desire for a base easily removed by washing with water • Characteristics of the surface to which it is applied Ex: an ointment is generally applied to dry skin; a cream is applied to wet surfaces. 8

9. Preparation of Ointments 1. Incorporation method: 2. Fusion method 9

10. 1. Incorporation method: • the active ingredient and the ointment base are mixed together until a uniform preparation is obtained • On a small scale, the pharmacist may mix the components using a mortar and pestle. On large scale (up to 1500 kg), ointments are manufactured in stainless steel tank which has a built-in mixer. • Before incorporation of the active ingredient, its the particle size should be reduced so final product will not be gritty or solids may first be dissolved in small amount of a solvent (e.g. water or alcohol), the solution is then mixed with the ointment base. Alcoholic solutions of small volume may be added easily to both oleaginous or emulsion bases. 10

11. Cont. Incorporation method: • Liquid drugs addition to oint base depend on ointment base’s capacity to accept the volume required. • For example, only very small amounts of an aqueous solution may be incorporated into an oleaginous ointment, whereas absorption bases readily accept more amounts of aqueous solutions. • When it is necessary to add an aqueous preparation to a hydrophobic base (such as oleaginous base), the solution first may be incorporated into a minimum amount of a hydrophilic base (such as absorption base) and then this mixture is added to the hydrophobic base. However, all bases, even if hydrophilic, have their limits to retain liquids, beyond which they become too soft or semiliquid. 11

12. 2-Fusion method: • all or some of the components of an ointment are melted together and cooled with constant stirring until congealed. • Components that not melted at the beginning (e.g. heat sensitive and volatile substances) are added last to the congealing mixture as it is being cooled and stirred. • Ointments containing components such as beeswax, paraffin, stearyl alcohol and high molecular weight PEGs are prepared by fusion.

13. Preservation used in case of ophthalmic preparations. topical preparations usually are not required to be sterile. However, preparations that contain water tend to support microbial growth to a greater extent than water-free preparations

14. Creams • semisolid preparations containing a medicinal agent dissolved or dispersed in emulsion. • After application of the cream, the water evaporates, leaving behind a thin film of the oleaginous component. • Creams used in topical skin, rectal and vaginal products. • Many patients and physicians prefer creams to ointments because they are easier to spread and remove.

15. Gel • Semisolid preparations consisting of medicinal agent dispersed in aqueous liquid rendered jelly-like by the addition of a gelling agent such as carbomer, CMC or HPMC. • Gels may thicken on standing and must be shaken before use to liquefy gel and enable pouring. • Medicated gels may be prepared for administration by various routes, including the skin, the eye, the nose, the vagina, and rectum.

16. Transdermal Drug Delivery Systems(TDDS): • are designed for the passage of drugs through the skin into the general circulation for their systemic effects. • TDDSmay be ointment, cream, gel or patch. However, transdermal patches are the most commonly used type, e.g., nitroglycerin patches, nicotine patches and estradiol patches.

17. Cont. Transdermal Drug Delivery Systems(TDDS): • Percutaneous absorption of a drug results from penetration (passive diffusion) of the drug through the stratum corneum. • After the stratum corneum, drug molecules pass through deeper epidermal tissues and into the dermis. When the drug reaches the vascularized dermal layer, it becomes available for absorption into the general circulation.

18. Cont. Transdermal Drug Delivery Systems(TDDS): • Normal unbroken skin acts as a natural barrier, limiting both the rate and degree of drug penetration. • layers of skin form barriers against permeation of external agents and loss of water from the body. Sebaceous glands, sweat glands, and hair follicles originating in the dermis and subcutaneous layers rise to the skin’s surface. • The stratum corneum is the horny layer which is dead epidermal cells. It contains 40% water, 20% lipid. • The stratum corneum, being keratinized tissue, behaves as a semipermeable membrane.

19. Cont. Transdermal Drug Delivery Systems (TDDS): • Hair follicles and gland ducts can provide rapid entry for drugs, but because their relative surface area is so small compared to the total epidermis, they have little effect on drug absorption • Drug blood levels achieved by transdermal delivery systems may be measured (by calculating the AUC) and evaluated against desired standard formula; but not used for topical nonsystemic products. • For topical preparations, the therapeutically effective drug concentration in the skin is not known, so treatment is based on qualitative measures

20. Factors Affecting Percutaneous Absorption • 1. Drug concentration • 2. The drug should have a greater attraction to skin than to vehicle. The aqueous solubility determines drug conc. that is ready for absorption while the lipid solubility influences rate of transport across the skin. so, drugs penetrate better in unionized form. • 3. Drugs with M.WT of 100 to 800 can penetrate skin. The ideal molecular weight of a drug for transdermal drug delivery is believed to be 400 or less. • 4. Hydration of the skin generally increases percutaneous absorption. Therefore, TDDS that utilizes an occlusive base may have more absorption than non occlusive types. • 5. Percutaneous absorption is greater when the TDDS is applied to a site with a thin horny layer than with a thick one.

21. Absorption Enhancers 1-Chemical Enhancers increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance such as increasing hydration of the stratum corneum, a change in the structure of the lipids and proteins denaturation. skin penetration enhancers; e.g., acetone, dimethyl sulfoxide, ethanol, polyethylene glycol, and sodium lauryl sulfate. The selection of a permeation enhancer should be based on its efficacy in enhancing skin permeation, its dermal toxicity and its compatibility

22. Cont. Absorption Enhancers 2-Physical Methods: such as iontophoresis. Iontophoresis is delivery of a charged compound across the skin membrane by using an electrical field. drugs have been subjected iontophoretic studies e.g., dexamethasone, propranolol, peptides, and insulin. It shows some success in peptide and protein administration.

23. Study release from TDDs The following methods are used: 1. In vivo method: by taking blood samples 2. In vitro method: skin permeation may be tested using various skin tissues (human skin, animal skin, or artificial skin) in a diffusion cell. In these systems, skin membrane or synthetic membranes may be employed as barriers to simulate the biologic system. The diffusion cell has two chambers, one on each side of the membrane.

24. Cont. Study release from TDDs • A temp-controlled solution of the drug is placed in one chamber and a receptor solution in the other chamber. When skin is used as test membrane, it separates the two solutions. Drug diffusion through skin may be determined by periodic sampling and assay of the drug content in the receptor solution. • The skin may be analyzed for drug content to show permeation rates and/or retention in the skin.

25. Suppositories

26. Suppositories • They are semisolid dosage forms intended for insertion into the body cavity (rectum, vagina and urethra) where they melt, soften, or dissolve and exert localized or systemic effect. • May be intended for retention within the cavity for either local or systemic action.

27. Advantages • 1-They offer a conventional means of administration for drugs which Irritate G.I.T. • 2- Supp. Offer easy means of administration for children and old persons. • 3-They can also be used for administration of drugs to unconscious patients. • 4-They can also be used for quick local action at the site of insertion.

28. Intended action • Local Action: Rectal supp. intendedto relieve constipation, pain, irritation, itching and inflammation associated with hemorrhoids and Vaginal supp. intended for localized effects are employed mainly as contraceptive, antiseptic…etc • Systemic Action: For systemic effects, the mucous membranes of the rectum and vaginapermit the absorption of many soluble drugs. Although the rectum utilized more for the systemic absorption of drugs than the vagina.

29. Some Factors Affecting on Drug Absorption from Rectal Suppositories 1-Physiologic Factors: - Colonic Content 2-Physicochemical Factors of Drug and Base: a-Physico-chemical Factors Related to Drug: including -Lipid-Water Solubility: - Particle Size: b-Physicochemical Factors Related to the Base

30. 1-Physiologic Factors: • The human rectum is approximately 15-20 cm in length. When empty of fecal material, the rectum contains only 2-3 ml of inert mucous fluid. There is abundant vascularization of the sub mucosal region of rectum wall with blood and lymphatic vessels. • Among the physiologic factors affecting drug absorption from the rectum are the colonic contents, circulation route and the pH of the rectal fluids. • -Colonic Content: When systemic effects are desired, a drug will have greater opportunity to make contact with absorbing surface of rectum and colon in the absence of fecal matter. Therefore, an evacuant enema may be administered before supp. Other conditions such as diarrhea, colonic obstruction due to tumorous growth, and tissue dehydration can influence the rate and degree of drug absorption from the rectal site

31. 2-Physicochemical Factors of the Drug and Supp. Base • a-Physicochemical Factors Related to Drug: including • -Lipid-Water Solubility: The partition coefficient of a drug is importantin the selection of base. A lipophilic drug distributed in a fatty supp. base in low conc. has less of tendency to escape to the surrounding aqueous fluids than would hydrophilic substance present in a fatty base.  • -Particle Size: For drugs present in supp. in the undissolved state, size of drug particle will influence its dissolution and its absorption • b-Physico-chemical Factors Related to the Base: The base must be capable of melting, softening, or dissolving to release its drug for absorption. If, the base interacts with the drug absorption will be impaired. Also, if the base irritating to the mucous membranes of the rectum, it may initiate bowel movement negating the possibility of a drug release and absorption.

32. Suppositories Bases Ideal supp. Vehicles or basesshould be • Melt at rectal temp. • Completely non-toxic & non irritant. • Compatible with a broad variety of a drug. • It has no other polymorph. • It shrink sufficiently on cooling (no need for lubricant) • It has wetting & emulsifying properties. • Water capacity is high (i.e. high percentage of water can be incorporated in it). • Stable on storage. (color,, odor or release ).

33. Classification of Supp.Bases I-Fatty vehicles • A-Cocoa butter (theobroma oil). • B- The semi synthetic type of fatty vehiclessuch as WitepsolH 15 • II-Water soluble vehicle. PEGs

34. I-Fatty vehicles (the fatty vehicles used nowdays are almost semi orfully synthetic ones). A-Cocoa butter (theobroma oil). was the most used supp. Base Since is non reactive and melts at body temp. Cocoa butter smells and tastes like chocolate. It's M.P. between 30oC and 35oC. -Cocoa butter is no longer used because of its many disadvantages. -Disadvantages: 1. slow cooling and if overheated, it form, on cooling, unstable polymorph 2. It shrinks only slightly on solidification hence mould lubricant is required. 3.It has a low absorptive capacity for water. 4.Chemical instability (prone to air oxidation and become rancid on storage ). 5.its melting point is usually reduced by addition of drugs such as volatile oils.

35. B- The semi synthetic type of fatty vehicles • They have few or none of the problem mentioned with cocoa butter,. EX:WitepsolH 15 disintegrates in rectum as fast as theobroma oil. The melting time of cocoa butter is 4 min while 6 mins. for witepsol. • The higher melting time of witepsol enables supp to ascend more in rectum before disintegration while theobromasupp melt at lower temp. more rapidly and more likely to cause leakage. • The witepsols are not subject to structural change at a temp. > M.P. • A high numbers means that power to absorb water is high, this may lead to increase rate of decomposition for drugs that are easily hydrolyzed, as aspirin. • Witepsolscontracts more upon solidification than cocoa butter, thus no need for lubricating the mold. Witepsol H15 can be mixed with other witepsols. • Witepsolssolidify rapidly after being poured into mold.

36. II-Water soluble vehicle • are much less in use because of their disadvantages. They contain a classical glycerin gelatin or soap bases which are used as laxative or in vaginal therapy. • The most popular water soluble vehicles are PEGs which termed carbowaxes; they exist in a M. wt range from 200 to 20000. • At room temp, the lower members of the series are liquid as PEG 400.PEG 1000 (macrogol 1000) is a soft solid and the higher members are wax like, they melt between 37°C and 63°C and are easily shaped into a supp.

37. Disadvantages of Macrogols Bases (PEG bases): • 1-They are hygroscopic and may cause dehydration of rectal mucosa. Such irritant effects can be reduced by immersing the supp. in water before insertion. • 2-They may be brittle unless molten base is poured into mould at low temp as possible. Brittleness can be reduced by the addition of surfactants or plasticizers such as castor oil or propylene glycol. • 3- good solvent properties of PEG may retard release of certain drugs. • 4-Crystal growth of suspended or partially dissolved drugs may occur in these bases. Such crystals may make the base brittle and may show delayed dissolution and irritant effects. • 5- incompatible with a number of medicaments and materials such as benzocaine, penicillins, phenols, salicylic acid, sulphonamides, tannic acid, sorbitol and some plastics.

38. Combinations • Several combinations of PEGs such as PEG 1000 and PEG 400 have been prepared for supp bases having different physical properties

39. Compressed tablet sup • Rectal supp usually are not compressed as tablets, because the amount of liquid in the rectal cavity is inadequate for tablet disintegration. • Effervescent base tablets have been described as a carbon dioxide releasing laxative supp. • Compressed tablets weighing about 3g are used as a vaginal supp. Fat base vaginal supp are sometimes rejected because of the discomfort resulting from the seepage obtained from the supp with water insoluble bases. • The compressed tablet for vaginal use is usually almond shaped to ease insertion and to provide maximum surface area to facilitate disintegration and dispersion of the drug

40. Choice of vehicle (base) • The points which are important for the choice: *Composition • *Melting behavior • *Rheological properties • * the volume of the suppository: Usually suppositories for adults are 2ml and for children 1 ml. the larger volume may encourage a reaction of the rectal wall, thus helping to spread the melt over a larger area. The increase of volume of, for example, paracetamol suppositories, resulted in faster and more complete absorption of the drug.

41. The drug -The factors related to the drug substance such as: 1-Drug solubility 2-Surface properties of drug 3-Particle size

42. Manufacturing process of suppositories: 1-Hand molding 2-Automatic machine molding as Rotary machine: 3-compression Moulding: made by compressing the cold grated mass by piston, so that mass is extruded into moulds. The cold compression method is simple and results in more elegant appearance than hand molding. It avoids sedimentation of the insoluble solids, but is too slow for large scale production. its major disadvantages in fat type base suppositories is air entrapment 4-Fusion molding or Pour Molding: in both laboratory and industry. First base is melted, preferably on a water bath to avoid overheating, and then active ingredients are wither emulsified or suspended in it. Finally, the mass is poured into cooled metal moulds.

43. SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES: • 1-Water in suppositories • 2-Hygroscopicity: • 3-Incomptability • 4-Viscosity: • 5-Brittleness: • 6- Volume contraction: • 7-Lubricants or mold release agents: • 8-Weight and volume control:

44. 1)Water in suppositories: • use of water should be avoided as a solvent in sup. bases for the following reasons. • accelerate the oxidation of fats. • Evaporation of water causes the crystallization of dissolved substances. • water at a higher concentration affect drug absorption only if an oil in water emulsion exist. • result in possible interaction to avoid this problem anhydrous bases are used. • Bacteriostatic agents should be used in case of water presence such as parabens to avoid the fungal growth and contamination.

45. 2-Hygroscopicity: Hygroscopic agents such as glycerin and gelatin in supp. lose moisture by evaporation in dry atmosphere and absorb moisture under condition of high humidity. PEG are also hyroscopic in nature but the rate of moisture change in PEG depends on the humidity and chain length of the molecule, as the chain length increases the hygroscopicity decreases.

46. 3-Incomptability • PEG bases are incompatible with silver salts, tannic acids and sulfonamides. Most of the chemical have the tendency to crystallize out of PEG. • Higher concentration of salicylic acid softens PEG to an ointment like consistency and aspirin complexs it.

47. 4-Viscosity: behavior of supp. in rectal region after melting depends on the viscosity of the supp. mass. Therefore supp with low viscosity bases extracare should be taken to avoid sedimentation of suspended particles, molten base must be handled at the lowest temperature necessary to maintain fluidity, continuous stirring without entrapping air and quickly solidified in the mold. to overcome the problems caused by low viscosity base. • using of Narrow melting range bases • 2% aluminium, monosterate used increases the viscosity of the fatty base, and maintaining a homogenous suspension of insoluble material.

48. 5-Brittleness: • Synthetic fatty bases which have a high degree of hydrogenation and stearate contents are brittle than cocoa butter sup.. • Fracturing is induced by rapid chilling of the melted base in an extremely cold mould. • To overcome temp. difference of temp. between melted base and mould should be lowered & using the small amount of tweens, castor oil, propylene glycol

49. 6- Volume contraction: occurs after cooling in the mould result in : 1) Good mould release. • hole formation at open end of mould. This unwanted effects results in lowered supp. weight and bad appearance of supp. & can be avoided by draining a mass slightly over its congealing temp. into a mould heated to about same temp.or the mould is over filled and the excess mass containing hole can be scrapped off. Lubricants or mold release agents using  in case of low volume contraction, mold lubricants are used ex: mineral oil, aqueous solution of sodium lauryl sulphate and various silicons and alcohol

50. 7-Weight and volume control: The amount of active ingredients or drug in each suppository depend on the following. 1. The amount of drug in the bulk 2. The capacity of the mold volume 3. The specific gravity of the base 4. The volume difference among the molds ±2% 5. Weight difference among suppositories due to improper manufacturing process. e.g. incomplete closing of molds, uneven scrapings (variations within ± 5%)