Formulation and evaluation of modified release oral solid dosage forms. prof. dr. Saša Baumgartner University of Ljubljana Faculty of Pharmacy

Transcription

1 Formulation and evaluation of modified release oral solid dosage forms prof. dr. Saša Baumgartner University of Ljubljana Faculty of Pharmacy Content Terminology Why modified release? How to select appropriate API Physiological consideration important at dosage from designing Types of modified release prolonged release Matrix systems Reservoir systems Osmotic controlled systems Gastric retentive dosage forms 1

2 Modified/conventional release Conventional release dosage form Preparations showing a release of API which is not deliberately modified by special formulation and/or manufacturing method. In case of a solid dosage form, the dissolution profile of API depends essentially on the intrinsic properties of API Synonymous: Immediate release dosage form Modified release dosage forms Preparations where the rate and/or place of release of API is different from that of the conventional dosage form administered by the same route. This deliberate modification is achieved by special formulation design and/or manufacturing method. Modified release dosage forms include: prolonged release delayed release pulsatile release. Modified release Prolonged release dosage forms Modified release dosage forms showing a slower release than that of the conventional release dosage form administered by the same route. Prolonged release is achieved by special formulation design/and/or manufacturing method. Synonymous: extended release dosage form Delayed release dosage form Modified release dosage forms showing a release of API which is delayed. Delayed release is achieved by special formulation design and/or manufacturing method. The release of API is delayed for a predefined period after administration or application of the dosage form and then releases as a conventional dosage form resulting in a lag time without any change in other pharmacokinetic parameters. Pulsatile drug release Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period 2

3 Some expressions regarding modified release Controlled-release Extended release Sustained-release Timed-release Long-acting Prolonged-action Sustained-action Why do we formulate modified release dosage forms? The main objectives is to produce safe, effective and patient-friendly drug delivery systems To reduce dosing frequency and thus increase acceptability by patients To increase the effectiveness of the API with a retention of the dosage form at the site of action To decrease API doses and at the same time to maintain an optimum concentration of API in plasma and in this way to reduce the side effects associated with fluctuations in the plasma concentrations of "classic" dosage forms To prolong the life cycle of the product 3

4 Comparison of plasma profils of API from conventional and prolonged release tablets Feasibility assessment of chemical entity for controlled release delivery Physical, chemical, biopharmaceutical therapeutic properties of API Solubility (if <0.01mg/mL inappropriate for incorporation into prolonged drug delivery systems) Dosage(max 1g) Stability (ph, enzymes, flora) Lipofilicity /permeability, absorption site Elimination t 1/2 (from 2 to 8 h) Therapeutic window the risk of overdose First-pass metabolism PK / PD ratio 4

5 The importance of physiological factors for proper formulation of prolged release dosage forms The variable physiological factors: ph enzymes The movement of GIT - mechanical stress Transit time through the GIT gastric emptying Passage through the small intestine Retention in the colon Pathologic conditions The possibility of local irritations (irritation of mucous membranes) Gastrointestinal tract 5

6 Total transit time of dosage forms through GIT Depends on the physiological conditions (in particular of the movement of the upper GIT) and the properties of dosage form most oral dosage forms with prolonged release passes through the places where the API can be absorbed faster than in 12 hours total transit time can be influenced only by keeping the dosage form in the stomach - prolonged GRT 6

7 The impact of GIT movements on transit of dosage forms gastric movement gastric emptying fasted fed fluids solid particles 4 phases (I)MMC peristalsis caloric content volume osmolarity, ph retention of dosage form in stomach particle size phase (I)MMC volume Motoric activity in fasted state 4 phases of (I)MMC cycle Trajanje Faza I (min) Faza II Faza III 5 15 Faza IV min 7

8 Transit time of some dosage forms Fluids and pellets (< 2mm) fast emptying from stomach Single-unit dosage forms FO (>7 mm) can stay in stomach for more than 10 h, if taken together with food Transit time through intestine for most dosage forms is 3-4 h Transit time can be prolonged only by retention of dosage form in the stomach Transit time through the places of drug absorption is important dosage forms with 12h of release can be designed (+ elimination time) Single vs multiple unit dosage forms Single-unit dosage forms Tablets, film coated tablets, matrix tablets, capsules Multiple-unit dosage forms Granules, pellets, micropellets, microspheres Advantages and disadvantages 8

9 Composition of modified release dosage forms (in general) API Controlled release substance Matrix former Membrane former Substances that modified properties of matrix or membrane Pore-formers Surface active substances Solubilazers/pH modifiers Lubricants Additional coatings for the delay of release Mechanisms of prolonged release Diffusion controlled release Erosion controlled release Dissolution controlled release Osmotically controlled release Ion-exchange controlled release These mechanisms carried out independently, together or sequentially 9

10 Diffusion controlled drug release Matrix systems Hydrophobic matrices (polyvinyl chloride, polyvinyl acetate, waxes, fatty acids, ethyilcellulose, copolymers of metacrylic acid) Hydrophilic matrices (HPMC, HPC, HEC, PEO, xanthan, sodium alginate, polyacrylic acid) Reservoir systems Insoluble polymers (ethyilcellulose, acrylates) + plasticizer + pore formers Tablets, granules, microspheres,... F ilm sk a o b lo g a u č in k o v in a re z e rv o a r učin kovina m atriks - ogrodje 10

11 Hydrophobic matrices Diffusion rate depends on: Surface Diffusion path Concentration gradient Diffusion coefficient Diffusion controlled release - theoretical background Fick s second law gets into more detail, telling us the rate at which concentration (C) is changing at any given point in time (t); D is diffusion constant and as a default is constant Analytical solutions equation with respect to certain boundary conditions C t x C D x C D y y z C D z 11

12 A simplified solution for description the diffusion-controlled release (Higuchi) The boundary conditions are hypothetical matrix system, which does not dissolve and does not swell maintenance of pseudo steady-state during the release (constant thickness of the diffusion layer and a constant concentration gradient, which is only possible if the particles are infinitely large and flat)?! particle diameter is smaller than the average distance of diffusion path of API through the polymer mesh sink conditions the diffusion coefficient in the matrix is constant only diffusion takes place The concentration of the API in the matrix is greater than its solubility in the polymer; no interaction between the API and a polymer (Higuchi) a simplified and idealized example of the release kinetics from the matrix system Q S D s C s p T 2 C 0 pc s t Q amount of released drug; D s diffusion coefficient in dissolution medium, C s drug solubility in medium; p porosity of matrix; T tortuosity of matrix; C 0 total amount of API in matrix Higuchi also assumed that the dissolution of the active ingredient is faster than its diffusion Q k 1 t 1 / 2 12

13 Hydrophilic matrix systems Named also swelling matrix systems The most important among modified release systems Hydrophilic polymers in contact with the medium swell, forming a hydrogel, which slowly erodes and through the gel API is diffusing Prolonged release matrix tablets Water Disentageling polymer molecules in water Swelling polymer with waterconcentration-gradient Non-swollen polymer 13

14 Analytical methods for investigation of hydrophilic matrix tablets Tip Tablet P. Colombo et al. Journal of Controlled Release 61 (1999) Texture profiling of the XLBG matrix after different times of swelling in water with 200 mm CaCl2 added. Pavli et al. E-polymers, 2009 Analytical methods for investigation of hydrophilic matrix tablets oscillatory rheometry gel Dependence of viscoelastic properties of 3% xanthan dispersion (G' and G'') from ionic strength (NaCl from 0.00 till 0.20 M. G'-full line in G'' dashed line: - water, - = 0.01M, - = 0.20M Baumgartner et al. Eur.J Pharm Biopharm

15 Composition of hydrophilic matrix tablets API Hydrophilic polymer (20 80%) Fillers influencing matrix properties (sugars, polyols, salts) Enable faster and more even hydration May cause cross-linking of polymer chains (alginate + calcium ions) Influence on ionization of API - solubility Solubilizers and ph modifiers lubricants Hydrophilic matrix tablets Is this really that simple?? 15

16 HPMC golden standard for matrix tablets - is there anything left HPMC batches of the same viscosity and substitution type, but with different substituent pattern: great influence on polymer erosion and drug release Anna Viridén et al. European Journal of Pharmaceutics and Biopharmaceutics, 2011 The influence of xanthan polymer structure on the drug release natural origin, biocompatible, GRAS quality XAN behavior is related to its polyelectrolyte nature candidate for controlled release formulations 16

17 r e le a s e d d r u g ( % ) Natural polymers: synrgistic effect between Xanthan gum (XAN) and locust bean gum (LBG) tim e (h ) X A N L B G X L B G = 3 :1 X L B G = 1 :3 X A N -C a C l2 L B G -C a C l2 X L B G = 3 :1 -C a C l2 X L B G = 1 :3 -C a C l2 Multi-layer tablets hydrophilic matrix tablets 17

18 Water uptake (%) Erosion (%) Carrageenan based matrix tablets Kappa (κ)-carrageenan Iota ()-carrageenan Doxazosin mesilate Lambda () - carrageenan Erosion and water uptake studies of ι-, κ-, and λ-carr matrices iota iota NaCl kappa kappa NaCl lambda lambda NaCl Time (h) iota iota NaCl kappa kappa NaCl lambda lambda NaCl Pavli M et ali, Int. J. Pharm, Time (h) 18

19 Dual release controll DM release from different CARR matrices at 37 C in a ph 7.0 phosphate buffer. Advantages of hydrophilic matrix tablets Simple manufacture (direct compression, all types of granulation) Most ingredients are relatively inexpensive and of GRAS quality Many of the active ingredients can be incorporated Complete matrix erosion Known manufacturing technology It is possible to achieve a variety of release profiles 19

20 Disadvantages of hydrophilic matrix tablets Release depends on water diffusion into matrix and API diffusion out of formed hydrogel Erosion can complicate the release Problematic scale-up Reservoir systems - mainly multiunit dosage forms Multi-unit dosage forms After application they are evenly distributed across the GIT and therefore a lower risk for local irritation and less likely for 'dose dumping' Multiple Unit Pellet System - MUPS ethyl cellulose film - to enable prolonged drug release 20

21 Composition of reservoir systems Core API Filler Solubilizer (can be, but not necessary) Coating Polymer Plasticizer Pore former (if necessary) Coloring agent The addition of pore-former (HPMC) in ethyl cellulose (EC) coated pellets influence drug release sugar core ( μm) dipiridamol (low soluble API, 20 mg) suspended into Opadry dispersion (HPMC E6 and PEG 400) and than it is by layering added to sugar cores Pellets with API were then coated by Surelease E dispersion (water dispersion of EC wit oleic acid as plasticizer) The influence of different ratios between EC (Surelease) coating and HPMC (Opadry) as pore former in it on the release of API 21

22 Dipiridamol release from EC coated pellets no pore former Dipiridamol release from pellets coated by EC/HPMC (coating12 % wg) 22

23 Press-coating release mechanism can be changed by different additives in coatings Water soluble API in core ; Coating from ethyl cellulose, additives of: spray-dried lactose (SDL) or HPMC Advantages and disadvantages of reservoir systems Advantages of multi-unit More uniform gastric emptying Less problems with dose dumping Adoption of appropriate kinetics Disadvantages Single unit systems - dose dumping Multi-unit systems can not stay prolonged time in stomach no influence on transit time More complicated production than matrix systems 23

24 Lipid matrix systems Diffusion, dissolution or erosion controlled release Direct compression, melting technologies Usual composition: API Lipid matrix former Melting T higher than 37 C, from 20 to 40% of total tablet mass Pore-former NaCl, sugars, polyols, API (20 30% of formulation) Solubilizer and ph modifier Lubricants Dissolution controlled release Low water soluble substance, inherently enable a prolonged release Highly soluble API can be incorporated into slow dissolving carrier a layer of API is exchanged with a layer slowly soluble coating (pulsatile release) particles are coated with different thick coatings - (initial dose, maintenance dose) 24

25 Noyes-Whitney equation for description of dissolution in steady state Dissolution process can be described also as layer by layer diffusion controlled process (SIMPLIFICATIONS!!!) dc dt k d A D C C A C C S h S dc/dt dissolution rate; k d - dissolution rate constant; C s saturated solubility; C conc. solute in medium; D diffusion coefficient; h thickness of diffusion layer; A surface of dissolving particle 25

26 The osmotically controlled release Elementary Osmotic Pump Core with API and osmotically active substances (osmogene) Semipermeable membrane with one or more laser drilled orifice Semipermeable membrane API Delivery orifice H 2 O osmogens H 2 O H 2 O Drug release from EOP Delivery orifice H 2 O Influx of water trough membrane into core of dosage forms. Dissolution of soluble components solution of API is forming H 2 O H 2 O H 2 O H 2 O Osmotic pressure forced API solution trough delivery orifice H 2 O API H 2 O Tablet membrane remains unchanged H 2 O 26

27 Drug release: dm dt dm dt t t AC h ACJ P W w P d AC Release rate is proportional with J W and can changed by changing: System size Osmotic pressure in system Permeability of membrane for water Membrane thickness h J w P W h = water flux into system P W = permeability of membrane for water = difference in osmotic pressure through membrane A = surface of the system h = membrane thickness C = conc. Od dissolved API in the core P d = permeability of membrane for API Semipermeable membrane Water permeable, non permeable for API Non deformable Thin coating for changing the tablet appearance Upper membrane layer Porous lower membrane layer core- tablet 27

28 OROS Push-Pull systems Semipermeable membrane Delivery orifice Layer with API core Before application After application Pushing layer OROS Push-Pull systems 28

29 Advantages and disadvantages of OROS systems Advantages They typically give a zero order release profile after an initial lag. Deliveries may be delayed or pulsed if desired. Drug release is independent of gastric ph and hydrodynamic condition; is minimally affected by the presence of food in gastrointestinal tract They are well characterized and understood. The release mechanisms are not dependent on drug. A high degree of in-vitro and in-vivo correlation (ivivc) is obtained in osmotic systems. The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters. Disadvantages Expensive If the coating process is not well controlled there is a risk of film defects, which results in dose dumping Size hole is critical Dose dumping How to prolong GRT? - and increase biologic availability - decrease of frquency of applications The most important characteristics of dosage forms to prolong GRT: size and density To prolong GRT: High density systems Systems of different geometric shapes Systems based on super-poruos biodegradable hydrogels Mucoadhesive systems Magnetic systems Floating systems 29

30 Mucoadhesive systems FO adheres to the surface of the gastric mucosa Examples of bioadhesive substances: partially cross-linked polyacrylic acid (Carbopol, Polycarbophil ), chitosan, polylactic acid, Na-alginate, Disadvantages : The surface of the mucosa, is completely renewed in three hours non-selective binding of the other substances present in the stomach improvements: More specific Mucoadhesive materials - lectins (binding to specific carbohydrates) There is still no success 30

31 Floating systems condition: (dosage form) < (gastric fluid) Hydrodynamically balanced systems(hbs) Gas forming floating systems Raft-forming systems - liquids Low core density systems Hydrodynamically balanced systems(hbs) Gel layer Floating tablet Gastric fluid, Density > 1 Density of swollen tablet < 1 Dry tablet core Diffusion of API Erosion layer 31

32 Gas forming floating systems Improved floating mechanism Bubble formation (decreasing density) composition: NaHCO 3 + citric acid Dry conditions at manufacture and keeping Single unit systems: all or nothing Multiparticulate systems Systems with low core density < 1 g/cm 3 no lag-time, immediate floating Oil or air is entrapped in core Multi-unit systems, microbaloons, crosslinked hollow microspheres (dried by lyophilization) The most promising floating systems Frequent water intake is necessary 32

33 Design of floating tablets investigation of tablet matrices (swelling, erosion,...) determination of tablet floating properties and selection of optimal matrix former incorporation of API optimization evaluation Floating properties of tablets H P M C E 4 M H P M C K 4 M H P M C K M HPC H EC p re ssure A B A B A B A B A B 1 < 1 > 2 4 < 1 > 2 4 < 1 > 2 4 < 1 3 / / 2 < 1 > 2 4 < 1 > 2 4 < 1 > ,3-1,5 / / 3 < 1 > 2 4 < 1 > > 2 4 > < 0,6 < 1 > > > > 2 4 / / 7-9 0, > > 2 4 > < 0,6 / / > < 0,6 A time - tablets took to emerge on water surface (min) B time - tablets took to sink (h) 33

34 Formulation of tablets with API Model API Appropriate ratio between API and polymer Low compressibility Poor floating properties High dosage Granulation and further tableting Standardization of manufacture Basic formulation HPMC K4M : API. Release evaluation Highuci kinetics 34

35 Optimization of floating properties and release Fast swellable polymer cetostearol Increased incorporation of API Ac-Di-Sol Primojel HPMC K100M Decreased release NaHCO 3 and citric acid Improved floating Highuchi kinetic 35

36 To conclude: For the successful development of the prolonged release dosage froms we need to combine knowledge from different fields: physiology pharmaceutical technology biopharmacy pharmaceutical chemistry Physics... Literatura Qiu Y. Zhang G. Research and Development Aspects of Oral Controlled-Release Dosage forms. In. Wise DL (ed). Handbook of Pharmaceutical Controlled Release Technology; Marcel Dekker, NY, Basel, P.L. Bardonneta, b, V. Faivrea, W.J. Pughc, J.C. Piffarettid and F. Falsona: Gastroretentive dosage forms: Overview and special case of Helicobacter pylori.journal of Controlled Release.Volume 111, Issues 1-2, 10 March 2006, Pages 1-18 Aulton s Pharmaceutics Ipd. 36