Mohs-Formulations,Delivery PDF

What’s in a medicine? Patients take dosage forms, not one the “drug” Why? how? Drug Formulation and Delivery 2 Outline Why are drugs formulated Main types of formulations for oral delivery Why and how controlled release is achieved Drug Formul...

What’s in a medicine? Patients take dosage forms, not one the “drug” Why? how? Drug Formulation and Delivery 2 Outline Why are drugs formulated Main types of formulations for oral delivery Why and how controlled release is achieved Drug Formulation and Delivery 3 Objectives Compare and contrast the formulation, application, and limitations of HGC and SGCs Understand why gelatin has been, until recently, almost universally used to make the capsule shell. Why is the shell of SGCs is “soft” Draw a diagram to illustrate the HGC vs. SGC formulation structure Describe the rotary die process. Explain the advantages of tablets as a drug delivery system. Explain the physicochemical and therapeutic reasons why solid oral dosage forms are coated. Explain the ideal drug release profile for a controlled release substance and two ways this is achieved. Drug Formulation and Delivery 4 Solid Dosage Forms Powders & Granules Tablets Capsules Solutions Many others, adhesive films, transdermal, sachets, seeds, etc Drug Formulation and Delivery 5 Why Pharmaceutical Dosage Forms? Safe and convenient delivery of accurate dosing Project drug substance from atmospheric oxygen or humidity (coated tablets) Protect drug substance from gastric acid after oral administration (enteric-coated tablets) Conceal bitter, salty or offensive taste or odor of a drug substance (capsules, coated tablets, flavored syrup) Provide liquid preparations of an insoluble or unstable drug in desired vehicle (suspensions) Provide rate-controlled drug action (controlled release tablets, capsules and suspensions) Provide site-specific drug delivery (rectal or vaginal suppositories) Drug Formulation and Delivery 6 Advantages of Solid Dosage Forms Convenient to carry, readily identified and easily taken. Longer shelf life before expiring. Efficiently produced. Easier to package, distribute, ship, and store. The dosing is more accurate, comparing to liquid formulation. Possibility of controlled drug delivery. Drug Formulation and Delivery 7 Disadvantages of Solid Dosage Forms Certain patients population may have difficulty swallowing large tablets or capsules. Solid dosage forms are not appropriate for patients who are unconscious or intubated. Solid dosage forms take longer to break down, dissolve, absorb, and distribute in the body. Therefore, solid dosage form may not fit for emergency intervention. Some drugs (esp. biologics) are not suitable is a solid dosage form Drug Formulation and Delivery 8 Influential Factors in Dosage Form Design Molecular Size and Volume Drug solubility and pH Partition Coefficient Polymorphisms Stability pKa/Dissociation Constant Particle size and dissolution rate Membrane permeability Drug Formulation and Delivery 9 Capsules  USP Definition Capsules are solid dosage forms in which the drug is enclosed within either a hard or a soft soluble container or ‘shell’. Filled capsules are generally swallowed whole. Sometimes caregivers may open the capsule and mix the drug with food/drink Drug Formulation and Delivery 11 General Background HGC = hard gelatin capsules SGC = soft gelatin capsules Capsules classified as hard or soft depending on nature of the shell (and contents) SGC made of more flexible, plasticized gelatin film than HGC. Contents are typically liquid. Most intended to be swallowed, although theoretically, can use for rectal or vaginal insertion or in other unit dosage forms. Gelatin by far is the most commonly used HGC material. Drug Formulation and Delivery 12 Advantages of HGCs Elegant Easy to use, convenient Smooth, slippery, easily swallowed Tasteless Economical Better bioavailability Diverse formulations i.e., beads, granules, microtablets, semisolids Drug Formulation and Delivery 13 Properties of Gelatin Molecular weight ~20-200 kDa Usually mixtures of Type A and B are used Bone gelatin contributes firmness but is hazy Pork skin gelatin contributes plasticity and clarity Two main physicochemical properties: Bloom strength: empirical measure of gel strength measured in Bloom gelometer weight in grams required to depress a standard plunger into the surface of 6.67% w/w gel Desirable bloom strengths: 150-280 g Viscosity Drug Formulation and Delivery 14 What makes gelatin “Ideal” for capsules? üGelatin swells but insoluble in cold water. It is readily soluble in water > 30-35ºC (gel temperature) üGelatin has the ability to form a thermally reversible gel üGelatin excellent film forming properties üGelatin freely soluble in the stomach secretions (main reason it still has limited number of competitors today) üAs a protein, gelatin is digested to amino acids that can be absorbed üToday, most of these properties are shared by special starches & grades of HPMC used for capsules Drug Formulation and Delivery 15 Disadvantages of HGCs Slower in production than tablet More expensive than tablet Some patients have difficulty in swallowing capsules i.e., adhere to esophagus. One study reported about 50% of capsules became lodged to esophagus although only 3% were aware of it. Religious/dietary concerns; Bovine spongiform encephalopathy Drug Formulation and Delivery 16 HGC Shells HGC contain between 13% and 16% moisture Must protect them from excessive humidity or they will distort and lose their rigid shape. Used to manufacture most of the commercially available medicated capsules Used by dispensing pharmacists in the extemporaneous compounding of prescriptions. Parts of the capsules are the shell and the cap Made from a mixture of gelatin, certified dyes, plasticizer (glycerin, sorbitol), preservatives (parabens derivatives). Are clear, colorless and relatively tasteless May be colored by FD&C and D&C dyes and may be made opaque by addition of titanium dioxide Drug Formulation and Delivery 17 HGC Excipients - diluents Lactose, starch, dicalcium phosphate Less common diluents include: Microcrytalline cellulose Calcium carbonate Magnesium carbonate Mannitol Magnesium Oxide Silica gel Starch Talc Drug Formulation and Delivery 18 Industrial Manufacture Major problems: Telescoping and/or denting during filling; separation of capsules. Thus, development of coni-snap caps – tampered tips, and ridges to prevent premature opening Involves force feeding of powder into base of capsule – usually some auger within the hopper Drug Formulation and Delivery 19 Industrial Manufacture Special features Sealing and banding: prevents separation, tamperproof (not safety proof) Self-locking caps: Snap-Fit, Coni-snap, coni-snap supra (Capsugel), Loxit (Pharmaphil). Drug Formulation and Delivery 20 Soft Gelatin Capsule (SGC) A soft gelatin capsule is a one-piece, hermetically-sealed formulation, SGC containing medication in a liquid or semi-liquid state that has been formed, filled, and sealed in one operation. Drug Formulation and Delivery 21 Shell Properties Similar to HGC, the basic component is gelatin; however, it is plasticized by the addition of glycerol, sorbitol, propylene glycol, polyethylene glycol (PEG) Other Ingredients may include o Dyes o Opacifiers o Preservatives o Flavors Residual moisture content between 6-10%. Drug Formulation and Delivery 22 SGC Formulation Structure Gelatin Antioxidant Plasticiser Opacifier Modifier Dye Water Flavor Entry or Solution or delayed suspension release of drug coating Drug Formulation and Delivery 23 ADVANTAGES of SGCs 1. Elegant 2. Easy to use, portable, convenient 3. Smooth, slippery, easily swallowed 4. Taste masking 5. Requires the drug to be liquid, or at least dissolved, solubilized, or suspended in a liquid vehicle. That is, it is a method to administer liquid drugs (e.g., clofibrate®, reduces serum triglycerides; is ethyl ester prodrug of clofibric acid, replaced by fenofibrate) or drugs in a liquid vehicle (e.g., digoxin, Lanoxicaps®). Drug Formulation and Delivery 24 ADVANTAGES of SGCs 6. Metered liquid fill very accurate (more accurate than powder fill). 7. Homogeneous – content uniformity of ± 3% reported. 8. Potential enhanced bioavailability/faster action of liquid formulation e.g., digoxin, temazepam, theophylline, and phenytoin. e.g., digoxin SGC (Lanoxicaps®). Dissolved in vehicle of PEG 400, ethanol, propylene glycol and water. Higher plasma levels, enhanced bioavailability Drug Formulation and Delivery 25 ADVANTAGES of SGCs 9. Improved stability e.g., against oxidation (Oil-soluble vitamins) 10. Variety of shapes and sizes 11. Theoretically for routes of administration other than oral e.g., topical, ophthalmic, rectal, vaginal 12. Decreased side effects e.g., ulceragenic potential of dexamethasone – disperses readily from SGC. Drug Formulation and Delivery 26 DISADVANTAGES of SGCs 1. Manufacture must be contracted out to limited number of machines that have technological support to make SGC 2. More expensive to make than tablets. 3. Drugs may migrate from vehicle into shell 4. Highly moisture sensitive. 5. Not for efflorescent or deliquescent agents. Drug Formulation and Delivery 27 SGC Formulation Formulation involves mostly LIQUID, not powder technology Materials generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness, and manufacturing efficiency. SGC contains a single liquid, a combination of miscible liquids, a solution of a drug in a liquid, or a suspension of a drug in a liquid The liquid contents must NOT have an adverse affect on the gelatin walls Drug Formulation and Delivery 28 Example Drugs Formulated in SGCs Most (not all) are water-insoluble drugs acetominophen, bisacodyl, chlorpromazine, digoxin, hydrocortisone acetate, indomethacin, mesalamine, miconazole nitrate, prochlorperazine, terconazole. Water-soluble drugs aminophylline, morphine SO4, hydromorphone HCl, dinoprostone (PGE2) Drug Formulation and Delivery 29 Tablets Tablets Tablets are solid dosage forms, prepared with suitable pharmaceutical excipients Prepared mainly by mechanical compression and sometimes by molding Vary in size, shape, thickness, weight, hardness, disintegration and dissolution characteristics Most popular of all dosage forms Drug Formulation and Delivery 31 Qualities of a Good Tablet Accurate & uniform weight Homogeneity Absence of incompatibilities Stability & hardness Ease of disintegration Reasonable size and shape Pleasing appearance Ease of manufacturing Economy of production Drug Formulation and Delivery 32 Tablets and Patient Advantages Disadvantages Accuracy of dosage Large tablets (high Compactness doses) may be difficult to swallow Portability Incompatibility with food Blandness of taste GI irritation Ease of administration Lower bioavailability Drug Formulation and Delivery 33 Tablets and Manufacturer Advantages Disadvantages Relatively easy to Time and effort for manufacture once development (more than formulation is optimized capsules) due to High production rate complex composition & (economical) manufacturing process Good chemical and Formulation challenges physical stability (longer Variety of ingredients shelf-life than liquids) (binders, disintegrants etc.) Drug Formulation and Delivery 34 Tablets and Manufacturer Advantages Disadvantages Convenient to package & Manufacturing process ship (due to physical challenges stability) Optimization of Ease of identification process that is (shape, color, imprints) robust and scalable Market preference Drug Formulation and Delivery 35 Types of Tablets Conventional (compressed) Multi-compressed Chewable Soluble Effervescent Sublingual Buccal Instantly disintegrating or rapidly dissolving tablets Molded tablets, tablet triturates, hypodermic tablets Controlled release Drug Formulation and Delivery 36 Compressed tablet components Diluents or fillers Binding agents (adhesives) Disintegrating agents (disintegrants) Glidants (antiadherents) Lubricants Other: color, flavors, surfactants Drug Formulation and Delivery 37 Compressed Tablets Prepared by single compression Contain various excipients (additives): Diluents or fillers, binders, disintegrants, lubricants, colorants and flavorants (if necessary) Used for oral, buccal, sublingual or vaginal administration May be coated after compression Drug Formulation and Delivery 38 Chewable tablets For children, administration of large doses, for patients who have difficulty swallowing or for rapid onset of action effect. “Smooth, Creamy” base: mannitol. Alternatively, sorbitol, glycine, lactose, dextrose. Disintegrants unnecessary. Prepared by wet granulation method. Often flavored. Examples: chewable antacids and antibiotics Drug Formulation and Delivery 39 Effervescent Tablet Reaction between sodium bicarbonate and carboxylic acids (tartaric + citric in a 2:1 molar ratio). Reason: increase dissolution rate, palatability Packaging: important, Al foil e.g., KCl: K+ Care, K-lyte, Klor-Con/EF e.g., Alka-seltzer (aspirin) Drug Formulation and Delivery 40 Effervescent tablet Drug Formulation and Delivery 41 Tablet dissolution and drug absorption Pharm Res (2017) 34:890–917 Drug Formulation and Delivery 42 TABLET COATING Why coat tablets or capsules? Mask taste, odor Provide physical and chemical protection Control release Protect drug from stomach acid Incorporate another drug or provide initial release. Improve pharmaceutical elegance Most coatings from sugar or polymers Drug Formulation and Delivery 43 Sugar coating Sealing: prevent moisture penetration Subcoating: round edges and build up mass syrup, PVP, gelatin, powdered sugar Smoothing coat: simple syrup Finishing: 1-2 coats of syrup Color coating - optional Printing: FDA 1995 product identification Polishing Drug Formulation and Delivery 44 Common Film Coating Polymers Water soluble HPMC, PVP, PEG Water-insoluble ethyl cellulose Enteric coating CAP (Cellulose acetate phthalate), CAB (Cellulose acetate butyrate), HPMC (Hydroxypropyl methylcellulose) Drug Formulation and Delivery 45  ACRYLIC (EUDRAGIT®) RESINS Drug Formulation and Delivery 46 Why enteric coating 1. Reduce gastric irritation: aspirin, diclofenac, divalproex sodium, naproxen. 2. Prevent degradation: dirithromycin, doxycycline hyclate, erythromycins, lansoprazole, omeprazole, pancreatic enzymes, pantoprazole, rabeprazole. 3. Local effect: mesalamine Drug Formulation and Delivery 47 Buccal & Sublingual Tablets Drug Formulation and Delivery 48 Bypass the first pass metabolism Drug Formulation and Delivery 49 Buccal tablets Intended to dissolve in buccal cavity (or gums) Usually designed to dissolve slowly. Prolonged effects – contains bioadhesive to adhere to inside of mouth. Duration of effect: 15-45 mins to 6-8 hours Fentanyl citrate (Actiq) intrabuccal/transmucosal lozenge. Ideal for drugs that can be destroyed or poorly absorbed in GI Local effects – mouth ulcers (directly on affected area). Lozenges (troches) Drug Formulation and Delivery 50 Sublingual Tablets Placed under the tongue Allow to dissolved Rapid effect Avoids first pass effect Examples: glyceryl trinitrate (rapid effect), testosterone (poor GI availability – no longer in US). Drug Formulation and Delivery 51 Major limitations of conventional oral formulations Inconvenience of drugs with short plasma half-lives Peak-valley plasma levels Patient compliance High oral doses to achieve therapeutic concentrations at site of action. Variation in oral absorption due to pH, food, transit time. Drug Formulation and Delivery 52 What do we want to achieve? Control rate of drug delivery (release). Control onset, duration, and intensity of effect. Control site of absorption Reduce total dose required. Improve bioavailability Improve safety (particularly of drugs with low TI) Improve efficacy of drugs with short plasma half- lives. Improve compliance. Drug Formulation and Delivery 53 Oral Controlled Release Terminology Controlled delivery Sustained delivery Prolonged delivery Delayed delivery Pulsed delivery, repeat action localized delivery Site-specific delivery, targeted delivery Drug Formulation and Delivery 55  IDEAL DRUG FOR OCR FORMULATION A low molecular weight, freely water-soluble drug that is well and/or predictably absorbed and metabolized after oral administration, with a low plasma half-life (< 8 h) and high therapeutic index (> 10). Formulation Strategies for CR formulations PHYSICAL (most common). Controlled dissolution, diffusion, disintegration (erosion), pH effects, osmosis, density. CHEMICAL - prodrugs. BIOLOGICAL e.g., antibodies MECHANICAL e.g., pumps PHARMACOLOGICAL. e.g. Probenecid-penicillin Drug Formulation and Delivery 57 PHYSICAL STRATEGIES Diffusion control Dissolution control Erosion (disintegration) Osmotic control pH dependent Ion-exchange Density control (low and high) Partition control (NOT for solid oral formulations) Drug Formulation and Delivery 58 Diffusion-based formulation Diffusion through semi-permeable membrane (film coating). Reservoir system Diffusion through nondisintegrating matrix (tablet but also semi-solid ointment or viscous liquid). Drug Formulation and Delivery 59 DIFFUSION (MATRIX OR RESERVOIR) Drug Formulation and Delivery 60 DIFFUSION CONTROLLED DELIVERY Diffusion is the mass transfer of drug molecules by random motion from a region of high concentration to lower concentration. 𝑀 𝐽= 𝑑𝑆 & 𝑑𝑡 J = flux, M = mass of drug, S = surface area, t = time Drug Formulation and Delivery 61 DIFFUSION CONTROLLED DELIVERY The diffusional flux is proportional to the concentration gradient, dC/dx. 𝑑𝐶 𝐽 = −𝐷 𝑑𝑥 D = diffusion coefficient of the drug in cm2/s C = drug concentration (g/mL) X = is the distance in cm of movement perpendicular to the barrier surface. As M is usually in g, J is usually g・cm-2s-1 Reservoir Drug Formulation and Delivery 62 DIFFUSION CONTROLLED DELIVERY Diffusion through insoluble, non-disintegrating matrix #" 𝐷𝜀 $ 𝑄= 2𝐴 − 𝐶! 𝐶! 𝑡 𝜏 D = diffusion coefficient, e = porosity of matrix, t = tortuosity of matrix, Cs = saturation solubility of the drug in the medium, A = amount of drug in the tablet. If matrix disintegrates, drug release rate depends on rate of disintegration, dissolution, or both. Matrix Drug Formulation and Delivery 63 Drug Formulation and Delivery 64 OROS Drug reservoir- conventional tablet coating - semipermeable Principle of operation: water flows into tablet due to osmotic pressure, at a rate controlled by permeability of membrane. Water dissolves drug, increases hydrostatic pressure inside tablet. Drug in solution forced to leave via orifice. Rate of release is constant as long as there is undissolved drug in tablet. Drug Formulation and Delivery 65 Advantages and Limitations of OROS Advantages Zero-order release for ~ 50-70 % drug release rate independent of pH. release rate independent of food in GIT release rate independent of GIT motility. Limitations G. I. transit time variable absorption Drug Formulation and Delivery 66 GITS or PUSH-PULL SYSTEM GITS = Gastrointestinal Therapeutic System. Drug and osmotic compartments separated by flexible membrane. Water drawn into osmotic compartment; increase in hydrostatic pressure pushes on flexible membrane forcing drug out of orifice. Drug Formulation and Delivery 67 Push-pull osmotic tablet Drug Formulation and Delivery 68 EXAMPLES OF OSMOTIC TABLETS Glucotrol XL Concerta Drug Formulation and Delivery 69