MONOLITHIC MATRICES-HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN HYDROCHLORIDE”
Dissertation Submitted to THE TAMIL NADU Dr.M.G.R. MEDICAL UNIVERSITY
Chennai-600032
In Partial fulfillment for the award of the degree of MASTER OF PHARMACY
IN
PHARMACEUTICS
Submitted by PRIYADHARSHINI.K
Reg.No-261810260
Under the guidance of
Dr. V. KAMALAKKANNAN, M.Pharm.,Ph.D.
Associate Professor, Department of Pharmaceutics.
J.K.K.NATTRAJA COLLEGE OF PHARMACY KOMARAPALAYAM-638183,
TAMILNADU.
APRIL-2020
This is to certify that the dissertation work entitled “FORMULATION AND IN VITRO EVALUATION OF HYDROPHILIC MONOLITHIC MATRICES-
HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN
HYDROCHLORIDE” submitted by student bearing Reg.No-261810260 to The Tamilnadu Dr. M. G. R. Medical University, Chennai, for the partial
fulfillment of the degree of MASTER OF PHARMACY was evaluated by us during the examination held on………
Internal Examiner External Examiner
CERTIFICATE
This is to certify that the work embodied in the dissertation
“FORMULATION AND IN VITRO EVALUATION OF HYDROPHILIC MONOLITHIC MATRICES-HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN HYDROCHLORIDE”submitted to The Tamilnadu Dr. M. G. R.
Medical University, Chennai, was carried out by Reg.No-261510260 for the partial fulfillment of the degree of Master of Pharmacy in under direct
supervision of Dr. V. KAMALAKKANNAN, M.Pharm., Ph.D Associate Professor, Department of Pharmaceutics, J.K.K.Nattraja College of Pharmacy, Komarapalayam, during the academic year 2019-2020.
Place: Kumarapalayam. Dr. R. Sambathkumar., M.Pharm., Ph. D.,
Date: Principal,
J.K.K. Nattraja college of Pharmacy, Komarapalayam - 638183
TamilNadu
CERTIFICATE
This is to certify that the work embodied in this dissertation entitled
“FORMULATION AND IN VITRO EVALUATION OF HYDROPHILIC MONOLITHIC MATRICES-HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN HYDROCHLORIDE”submitted to The Tamil Nadu DR. M.G.R.
Medical University, Chennai, in partial fulfillment to the requirement for the award of degree of MASTER OF PHARMACY is a bonafied work carried out by Reg. No- 261810260 during the academic year 2019-2020, under my guidance and direct supervision in the department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
Dr.V.Kamalakkannan., M.Pharm.,Ph.D Dr.R.Sambathkumar., M.Pharm., Ph.D.,
Associate Professor, Principal,
Department of Pharmaceutics, J.K.K.Nattraja college of Pharmacy, J.K.K.Nattraja college of Pharmacy, Kumarapalayam – 638183
Kumarapalayam-638183. TamilNadu
Tamil Nadu.
Place : Kumarapalayam.
Date :
CERTIFICATE
This is to certify that the dissertation entitled “FORMULATION AND IN VITRO EVALUATION OF HYDROPHILIC MONOLITHIC MATRICES-
HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN
HYDROCHLORIDE” a bonafied work done by Reg.No- 261810260 J.K.K.Nattraja College of Pharmacy, in part and fulfillment of the university rules and
regulation for award of Master of Pharmacy under my guidance and supervision during the academic year 2019-2020.
Dr.V.Kamalakkannan., M.Pharm.,Ph.D Dr.R.Sambathkumar., M.Pharm., Ph.D.,
Associate Professor, Principal,
Department of Pharmaceutics, J.K.K.Nattraja college of Pharmacy, J.K.K.Nattraja college of Pharmacy, Kumarapalayam – 638183
Kumarapalayam-638183. TamilNadu
Tamil Nadu.
Dr.S.Bhama, M.Pharm., Ph.D.,
Head of the Department, Department of Pharmaceutics, J.K.K.Nattraja College of pharmacy,
Kumarapalayam-638183 Tamil Nadu
DECLARATION
The work presented in this dissertation entitled“FORMULATION AND IN VITRO EVALUATION OF HYDROPHILIC MONOLITHIC MATRICES-
HYDROGELS DRUG DELIVERY SYSTEM OF PRAZOSIN
HYDROCHLORIDE” was carried out by me, under the direct supervision of Dr. V.
KAMALAKKANNAN, M.Pharm., Ph.D Associate. Professor, Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
I further declare that, the work is original and has not been submitted in part or full for the award of any other degree or diploma in any other university.
Place: Kumarapalayam. Reg. No. 261810260
Date:
DEDICATED TO MY BELOVED
FAMILY,
STAFFS AND
FRIENDS
ACKNOWLEDGEMENT
I am proud to dedicate my deep sense of gratitude to the founder, (Late) Thiru J.K.K. Nattaraja Chettiar, providing us the historical institution to study.
My sincere thanks and respectful regards to our reverent Chairperson Smt.
N.SENDAMARAAI, B.Com., Managing Director Mr.S.OMM SHARRAVANA, B.Com., LLB., J.K.K. Nattraja Educational Institutions, Komarapalayam for their blessings, encouragement and support at all times.
It is most pleasant duty to thank our beloved Principal Dr.R.SAMBATHKUMAR, M.Pharm., Ph.D., J.K.K. Nattraja College of
Pharmacy, Komarapalayam for ensuring all the facilities were made available to me for the smooth running of this project.
I express my whole hearted thanks to my guide Dr. V. KAMALAKKANNAN M.Pharm., Ph.D Associate. Professor, Department
of Pharmaceutics, for suggesting solution to problems faced by me and providing indispensable guidance, tremendous encouragement at each and every step of this dissertation work. Without his critical advice and deep-rooted knowledge, this work would not have been a reality.
My sincere thanks to Dr. R. SHANMUGA SUNDARAM, M.Pharm., Ph.D., Vice Principal and Professor and Head of the Department, Department of Pharmacology, Dr.Kalaiarasi., M.Pharm., Ph.D Asst. Professor, Department of Pharmacology, for their valuable suggestions during my project work.
It is my privilege to express deepest sense of gratitude toward Dr. M.
Senthilraja, M. Pharm., Ph.D., Professor and Head, Department of Pharmacognosy and Mrs.P. Meena Prabha, M.Pharm., Asst. Professor, Department of Pharmacognosy for their valuable suggestions during my project work.
My sincere thanks to Dr. M. Vijayabaskaran, M.Pharm., Ph.D., Assistant Professor and head Department of Pharmaceutical chemistry Mrs. S. Gomathi, M.Pharm., Lecturer, Department of Pharmaceutical chemistry and for their valuable suggestions and inspiration.
My sincere thanks to Dr.N.Venkateswaramurthy, M.Pharm., Ph.D Professor and Head, Department of Pharmacy Practice. Mrs. K.Krishna Veni, M.Pharm., Asst. Professor, Department of Pharmacy Practice, for their help during my project.
My sincere thanks to Dr.V.Sekar, M.Pharm., Ph.D., Professor and Head of The Department of analysis, and Dr. I. Carolinenimila, M.Pharm., Ph.D., Assistant Professor, Department of Pharmaceutical Analysis for their valuable suggestions.
My sincere thanks to Dr.S. Bhama, M.Pharm., Ph.D Associate Professor, Mr. R. Kanagasabai, B.Pharm. M.Tech., Assistant Professor, Mr.K. Jaganathan, M.Pharm., Asst.Professor, Department of Pharmaceutics, Mr. C. Kannan M.Pharm., Asst. Professor, Department of Pharmaceutics for their valuable help during my project.
I greatly acknowledge the help rendered by Mrs. K. Rani, Office Superintendent, and Mrs. S. Jayakala, B.A., B.L.I.S., Asst. Librarian fortheirco- operation.
My special thanks to all the Technical and Non Technical Staff Members of the institute for their precious assistance and help.
Last, but nevertheless, I am thankful to my lovable parents and all my friends for their co-operation, encouragement and help extended to me throughout my project work.
Reg.No:261810260
CONTENTS
CHAPTER TITLE PAGE NO
I INTRODUCTION 1
II REVIEW OF LITERATURE 19
III AIM AND OBJECTIVE 21
IV PLAN OF WORK 23
V DRUG AND EXCIPIENTS PROFILE 24
VI METHODOLOGY 36
VII RESULTS AND DISCUSSION 50
VIII SUMMARY & CONCLUSION 94
IX BIBLIOGRAPHY 97
LIST OF FIGURES
Figure No. Figures Page No.
Figure 1 Diffusion controlled monolithic-matrix delivery system 9
Figure 2 Dissolution controlled monolithic-matrix delivery
system 10
Figure 3 Drug release from hydrogel based DDS 11
Figure 4 Mode of action of hydrophilic matrix dosage form 12
Figure 5
UV spectrum of prazosin hydrochloride in 0.1 N HCl
solution (10 g/ml). 38
Figure 6 Calibration curve of prazosin hydrochloride in 0.1 N
HCl solution 39
Figure 7
UV spectrum of prazosin hydrochloride in phosphate
buffer solution, pH 7.2 (10 g/ml). 40
Figure 8 Calibration curve of prazosin hydrochloride in
phosphate buffer solution, pH 7.2 41
Figure 9 FTIR of prazosin hydrochloride (pure) 51
Figure 10 FTIR of prazosin hydrochloride + Xanthan gum 52 Figure 11 FTIR of prazosin hydrochloride + ethyl cellulose 52 Figure 12 FTIR of prazosin hydrochloride + guar gum 53 Figure 13 FTIR of prazosin hydrochloride + HPMC K 100 53 Figure 14 FTIR of prazosin hydrochloride + HPMC K 4 M 54
Figure 15 FTIR of formulation-10 54
Figure 16 Comparison of in vitro release of prazosin
hydrochloride from marketed tablets 57
Figure 17
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-I, F-II, F- III, and marketed product.
61
Figure 18
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-IV, F-V, F- VI, and marketed product.
65
Figure 19
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-VII, F-VIII, F- IX, and marketed product.
68
Figure 20
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-IX at different medium containing different concentration of SLS
75
Figure 21
Comparison of in vitro release of prazosin hydrochloride from tablets of F-IX and marketed product at different volume of medium
76
Figure 22 Comparison of in vitro release of prazosin
hydrochloride from tablets of F-IX at different medium. 78
Figure 23
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-IX at different rotational speeds.
80
Figure 24 In vitro release of prazosin hydrochloride from tablets of
F-IX of firstand second (reproducible) trial 82
Figure 25
In vitro release of prazosin hydrochloride tablets from F-IX on zero dayand after one month of accelerated stability studies
84
Figure 26 In vitro release profile of prazosin hydrochloride from
tablets of F-IX fitted in zero order release 86
Figure 27 In vitro release profile of prazosin hydrochloride from
tablets of F-IX fitted in first order release 87
Figure 28 In vitro release profile of prazosin hydrochloride from
tablets of F-IX fitted in Higuchi’s Plot 88
Figure 29 In vitro release profile of prazosin hydrochloride from
tablets of F-IX fitted in Hixon- crowel Plot. 88
Figure 30 In vitro release profile of prazosin hydrochloride from
tablets of F-IX fitted in korsmeyer's-peppas Plot 90
Figure 31 water uptake and swelling study of prazosin
hydrochloride tablets from F-IX 92
LIST OF TABLES
Table No. Tables Page No.
Table 1 Classification of sustained/controlled release systems 5
Table 2 Parameters for drug selection 7
Table 3 Pharmacokinetic parameters for drug selection 8
Table 4 Various drugs formulated as sustained release matrix
tablets using different techniques 16
Table 5 Data for calibration curve of prazosin hydrochloride in 0.1 N HCl solution at 330.4 nm
39
Table 6 Data for calibration curve of prazosin hydrochloride in phosphate buffer solution, pH 7.2 at 340.4 nm
41
Table 7 Comparison between angle of repose and flow property 43 Table 8 Formulations of prazosin hydrochloride tablets 45
Table 9 Wave number of functional groups of prazosin
hydrochloride 51
Table 10 Physical parameters of prazosin hydrochloride 55
Table11 Evaluation of the marketed tablets of prazosin
hydrochloride (5 mg) 55
Table12 Dissolution profile of Minipress XL and Prazopress XL
in 0.1 N HCl solution. 56
Table13 Physical properties of the blends of tablet batches
prepared with xanthan gum of different concentrations 59
Table14 Properties of the matrix tablets prepared using different
concentrations of xanthan gum 59
Table15 In vitro release of prazosin hydrochloride from tablets of
F-I to F-III 60
Table 16 Comparison of f1 and f2 values for the tablets of the
batch F-I to F-III. 62
Table17
Physical properties of the tablets prepared using combination of xanthan gum and ethyl cellulose/ guar gum.
63
Table18
Properties of the matrix tablets prepared using
combination of xanthan gum and ethyl cellulose/ guar gum.
63
Table19 In vitro release of prazosin hydrochloride from the
tablets of F-IV to F-VI 64
Table 20 Comparison of f1 and f2 values for the tablets of the
batch F-IV to F-VI 66
Table 21 Physical properties of the blend of tablet batches
prepared with HPMC K4M and HPMC K 100 66
Table 22 Properties of the matrix tablets prepared using HPMC
K4M and HPMC K 100 67
Table 23 In vitro release of prazosin hydrochloride from tablets of
F-VII to F-IX 68
Table 24 Comparison of f1 and f2 values for the tablets of the
batch F-VII to F-IX 70
Table 25 Comparison of tablets of F-IX with the marketed
product (Minipress XL) 70
Table26
Comparison of in vitro release of prazosin
hydrochloride from tablets of F-IX with marketed product
71
Table 27 In vitro release of prazosin hydrochloride tablets 72
Table 28
In vitro release of prazosin hydrochloride from F-IX in different mediumcontaining different concentration of SLS
74
Table 29 In vitro release of prazosin hydrochloride from F-IX in
different volume of medium 76
Table 30 Comparison of f1 and f2 values for the tablets of the
batch F-IX with marketed product. 77
Table 31 In vitro release of prazosin hydrochloride from F-IX in
different medium 78
Table 32 Comparison factors of tablets of F-IX on firstand second
medium 79
Table 33 In vitro release of prazosin hydrochloride from F-IX in
different agitational intensity 80
Table 34
In Vitro release of prazosin hydrochloride from tablets of F-IX of first and second (for confirmation of
reproducibility) trials in 0.1N HCl
82
Table 35 Comparison factors of tablets of F-IX on firstand second
(reproducible) batches 83
Table 36
In Vitro release of prazosin hydrochloride from tablets of F-IX on zero day and samples after one month accelerated stability studies
84
Table 37 Comparison factors of F-IX tablets on zero dayand after
one month 85
Table 38
In Vitro release of prazosin hydrochloride from tablets
of F-IX 85
Table 39 Comparison of orders of in vitro release of prazosin
hydrochloride from tablets of F-IX 87
Table 40 Regression equations of in vitro Release of prazosin
hydrochloride from tablets of F-IX 89
Table 41 Swelling behavior and water uptake studies of F-IX
tablets 91
LIST OF ABBRIVATIONS
CDDS Controlled drug delivery system CRDF Controlled release drug formulation DDS Drug delivery system
F1 Difference factor F2 Similarity factor GIT Gastrointestinal tract
HPMC Hydroxy propyl methyl cellulose LBD Loose bulk density
Rpm Rotations per minute RH Relative humidity
SC Standard concave
TBD Tapped bulk density SLS Sodium lauryl sulphate BPH Benign prostatic hyperplasia SD Standard deviation
FT-IR Fourier transform infrared spectroscopy
AM Average mean
Vd Volume of distribution
MEC Minimum effective concentration MTC Maximum toxic concentration HPC Hydroxypropyicellulose
ABSTRACT
Sustained release formulation of prazosin hydrochloride based on monolithic - matrix technology was developed and evaluated. Prazosin hydrochloride is a very slightly soluble in water so it is suitable to develop sustained release matrix tablet using hydrophilic polymers. As prazosin hydrochloride is a short acting drug, so developed formulation provides the advantages of sustained release formulations.
The developed formulation is equivalent to the commercial marketed product in view of its in vitro release. The developed formulation has an additional advantage like less steps of manufacturing procedure and is therefore economical. All of which made the procedure easily amenable to mass production using conventional tablet machines. Prazosin hydrochloride matrix tablet formulations were prepared with different compositions using different polymers. Finally, one optimized formula for matrix tablet was selected and studied in detail. The effect of formulation variables namely different polymers and concentration of polymer were studied. Prazosin hydrochloride release was directly proportional to the polymer concentration. Drug release from the developed formulations was independent of pH of the release medium but dependent on the agitational intensity of tablet. Prazosin hydrochloride release from the developed matrix formulation follows zero-order and diffusion is found to be the main mechanism of drug release. The manufacturing procedure was found to be reproducible and formulations were stable after one month of accelerated stability studies. The swelling studies shows good result for formulation F-IX.
Keywords: Prazosin hydrochloride; sustained release; matrix tablet; formulation;
evaluation; in vitro release; stability; swelling.
I. INTRODUCTION
Oral ingestion is the traditionally preferred route of drug administration, providing a convenient method of effectively achieving both local and systemic effects. In conventional oral drug delivery systems, there is very little control over release of the drug. The effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses. Which in most situations, often results in constantly changing, unpredictable and often sub-or-supra therapeutic plasma concentrations leading to marked side effects.1 Some limitations associated with such a conventional dosage form are as follows;2
1. Poor patient compliance; increased chances of missing the dose of a drug with short half-life for which frequent administration is necessary.
2. A typical peak plasma concentration time profile is obtained which makes attainment of steady state condition difficult.
3. The unavoidable fluctuation in the drug concentration may lead to under medication or over medication as the steady state concentration values fall or rise beyond the therapeutic range.
To overcome all this, it would be advantageous and more convenient to maintain the dosing frequency to once, or at most twice-daily. An appropriately designed sustained release dosage form can be a major advance in this direction compared to conventional immediate release dosage forms.3 The development of improved method of drug delivery has received a lot of attention in the last two decades.4
This technique for the drug administration is termed ‘sustained release’ or
‘controlled release’. It is based on the concept of implanting into the body, a reservoir of a drug contained in a special biodegradable polymeric carrier material.5 The overall objective is that, once the drug/carrier material has been injected, or otherwise implanted or taken orally into the body, the drug is released at some predetermined rate for some desired period of time.6
In the last few years controlled release dosage forms have made significant progress in terms of clinical efficacy and patient compliance. The objective of
and maintain a constant drug blood level. Moreover these dosage forms have been specially designed to release the drug slowly over several hours, to protect the drug from the low pH of the stomach, and/or to protect the stomach from the irritating effects of the drug. Key advantages to the use of this technology are prolonged activity, fewer doses, fewer side effects and reduced toxicity. Too much of medicine ingested or injected all at once in order to have a maintenance concentration can mean wasted material or toxic side effects. By decreasing the dose rate, it is possible to avoid these problems and to find a better efficacy results. A major objective of the controlled release scientist is to determine the best speed of release to obtain optimal performance.7
Introduction of matrix tablet as sustained release dosage form has given a new breakthrough for novel drug delivery system in the field of pharmaceutical technology. It excludes complex production procedures such as coating and pelletization during manufacturing and drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used in the preparations.8
The use of polymeric matrix devices to control the release of a variety of therapeutic agents has become increasingly important in the development of modified release dosage forms. A matrix device is a drug delivery system in which the drug is dispersed either molecularly or in particulate form within a polymeric network. The device may be a swellable hydrophilic monolithic system, an erosion-controlled monolithic system or a non-erodible system.9 In particular;
the interest awakened by matrix type deliveries is completely justified in view of their biopharmaceutical and pharmacokinetics advantages over the conventional dosage forms. These are the systems for delay and control release of a drug that is dissolved or dispersed in a resistant support to disintegration.10
Matrix devices have a major advantage over other controlled release devices, as they cannot undergo sudden dose dumping. This gives a higher initial release rate and thus can be made to release at a nearly constant rate. The polymer when incorporated into pharmaceutical dosage forms such as tablets has shown a tendency to linearise the drug release curves and shows zero order release.11Oral controlled release dosage form is a drug delivery system that provides the continuous oral
delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system that targets the delivery of a drug to a specific region within the GI tract for either a local or systemic action.15
This ideal dosing regimen, which enhances patient compliance, guard against overdosing and side effects, is made possible by controlled release delivery systems, which use a variety of mechanisms to deliver and maintain the drug at a certain level in the patient’s blood stream.16
Controlled Release Drug Delivery System
The newer drug delivery systems are being investigated so as to alter the body distribution of drug(s) with a view to reduce the toxicity of drug and/or deliver them more efficiently to their site of action.
In generalized way, the sustained release or controlled release systems are intended to exercise control on drug release in the body, whether this be of a temporal or spatial nature or both: In other words, the system attempts to regulate drug concentrations within the tissue or cells.17
The sustained or controlled delivery attempts to,
Sustain drug action at predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a saw tooth kinetic pattern
Localize drug action by spatial placement of a controlled release system (usually rate controlled) adjacent to or in the diseased tissue or organ.
Idealistically to maintain a constant drug level in either plasma or target tissue, release rate from a controlled release system should be equal to the elimination rate from plasma or target tissue. The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of therapeutically active moieties by using either polymer or by modifying parameters inherent in a selected route of administration.17
Basically, there are three modes of sustained drug delivery, i.e. targeted delivery, controlled release, and modulated release. Targeted delivery refers to the
specific cell types, tissues of organs. Controlled release refers to the use of a delivery device with the objective of releasing the drug into the patient body at a predetermined rate, or at specific times or with specific release profiles. On the other hand modulated release implies use of a drug delivery device that release the drug at variable rate controlled by environmental conditions, biofeedback, and sensor impute of an external control device.
In the field of pharmaceuticals, sustained release systems have been widely used in oral medication, since early 1950s. Perhaps the earliest examples are enteric- coated orally ingested tablets. Other slow release systems include encapsulated pellets of beads, sparingly soluble salts, complex systems, dug embedded in matrix, ion exchange resins, and swelling hydrogels. Most of the early products can be classified under sustained delivery systems, which means the release of active agent is slower than any conventional formulation, but is significantly affected by an external environment. In contrast, controlled release systems provide a release profile independent of external environment and predominantly controlled by the design of the system.15
The enormous problems of patient compliance as well as the therapeutic desirability of controlled tissue drug levels over the time course of therapy are sufficiently compelling reasons to warrant placement of drugs in a sustained form of drug delivery.18
In the past, many of the terms were used to refer the therapeutic systems of controlled and sustained release have been used in an inconsistent and confusing manner. Sustained release, sustained action, prolonged action, controlled release, extended action, timed release, depot, and repository dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.19
Modified-release delivery systems may be divided conveniently into four categories:
1. Sustained release 2. Delayed release
3. Site-specific targeting 4. Receptor targeting Sustained Release Preparations
Sustained-release systems include any drug-delivery system that achieves slow release of drug over an extended period of time. If the systems can provide some control, whether this is of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered a controlled release system.20
Table 01:Classification of sustained/controlled release systems15
Type of system Rate-control mechanism
Diffusion controlled Reservoir system Monolithic system
Diffusion through membrane Diffusion through membrane Water penetration
controlled Osmotic system Swelling system
- transport of water through semipermeable membrane - water penetration into glossy polymer
Chemical controlled Monolithic system
Pendant system
Ion exchange resins
- Surface erosion or bulk erosion
- Hydrolysis of pendent group and diffusion from bulk polymer
-Exchange of acidic or basic drugs with the ions present on resins.
Regulated system
Magnetic, Ultrasound - External application of magnetic field or ultrasound to device
Advantages of Sustained Release Products
1) Decreased local and systemic side effects:
Reduced gastrointestinal irritation.
2) Better drug utilization:
Reduction in total amount of drug used.
Minimum drug accumulation on chronic dosing.
3) Improved efficiency in treatment:
Optimized therapy.
Reduction in fluctuation in drug level and hence more uniform pharmacological response.
Special effects e.g. sustained release aspirin provides sufficient drug so that on awakening the arthritic patient gets symptomatic relief.
Less reduction in drug activity with chronic use.
Improve the bioavailability of some drugs e.g. drugs susceptible to enzymatic inactivation can be protected by encapsulation in polymer systems suitable for sustained release.
4) Improved patient compliance:
Less frequent dosing
Reduced night-time dosing 5) Economy:
Although the initial unit cost of sustained release products is usually greater than that of conventional dosage forms because of the special nature of these products, the average cost of treatment over an extended time period maybe less.18
Disadvantages of Sustained Release Products
Some of the disadvantages of oral sustained release dosage forms are as follows, 1) Toxicity due to dose dumping.
2) Increased cost.
3) Unpredictable and often poor in vitro- in vivo correlation.
4) Risk of side effects or toxicity upon fast release of contained drug (mechanical failure, chewing or masticating, alcohol intake).
5) Local irritation or damage of epithelial lining (lodging of dosage forms).
6) Need for additional patient education and counseling.
7) Increased potential for first- pass clearance.
Biological Factors Influencing Oral Sustained-Release Dosage Form Design
Biological half-life.
Absorption and Metabolism.
Physicochemical Factors Influencing Oral Sustained-Release Dosage Form Design
Dose Size :( single dose of 0.5 – 1.0 g).
Ionization, pka, and aqueous solubility.
Partition coefficient and Stability.
Drug Selection for Oral Sustained Release Drug Delivery Systems21, 22
The biopharmaceutical evaluation of a drug for potential use in controlled release drug delivery system requires knowledge on the absorption mechanism of the drug form the G. I. tract, the general absorbability, the drug’s molecular weight, solubility at different pH and apparent partition coefficient.
Table 02:Parameters for drug selection Parameter Preferred value Molecular weight/ size < 1000
Solubility > 0.1 mg/ml for pH 1 to pH 7.8 Apparent partition coefficient High
Absorption mechanism Diffusion
General absorbability From all GI segments
Release Should not be influenced by pH and enzymes
The pharmacokinetic evaluation requires knowledge on a drug’s elimination half- life, total clearance, absolute bioavailability, possible first- pass effect, and the desired steady concentrations for peak and trough.
Table 03:Pharmacokinetic parameters for drug selection
Parameter Comment
Elimination half life Preferably between 0.5 and 8 hours Total clearance Should not be dose dependent Elimination rate constant Required for design
Apparent volume of distribution (Vd)
The larger Vd and MEC, the larger will be the required dose size.
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate
Therapeutic concentration (Cssav)
The lower Cssav and smaller Vd, the loss among of drug required
Toxic concentration
Apart the values of MTC and MEC, safer the dosage form. Also suitable for drugs with very short half-life.
Different Types of Matrices Used as Oral Sustained Release Drug Delivery System i.e.10
1. Hydrophobic matrix tablets 2. Hydrophilic swellable matrix
3. Floating type drug delivery system (gastro retentive drug delivery system)
Zone 1 Zone 2 Zone 3 Erosion front
Swelling front
Diffusion front
4. Complex reservoir or multi layered matrix
5. Bioadhasive or mucoadhesive drug delivery system 6. Beads and Pellets
7. Microcapsules and micro tablets
Among various technologies available, monolithic matrices continue to be popular because of simplicity in processing technology required, reproducibility and stability of the materials and dosage forms as well as ease of scale-up operation.
Polymers are used to control the release of drugs from different dosage forms administered orally. In particular, water-soluble cellulose ether [e.g.
hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC)], polyethylene oxide, polyvinyl alcohols, carbopol and polysaccharides such as xanthan gum, chitosan, alginic acid, pectin and guar gum have been extensively used.23
Commonly Used Monolithic-Matrix Controlled Drug Delivery Systems Diffusion Controlled Monolithic-Matrix Delivery System (15, 24, 25, 26)
In this type of controlled drug delivery system, the drug reservoir results from the homogeneous dispersion of the drug particles in either a lipophillic or a hydrophilic polymer matrix.
Figure 01: Diffusion controlled monolithic-matrix delivery system Zone 1: Undissolved drug, glassy polymer layer.
Zone 2: Undissolved drug, gel layer.
Gel layer thickness = Difference between erosion and swelling front position.
To formulate such systems, polymer and active agent are mixed to form a homogenous system. Diffusion occurs when the drug passes from the polymeric matrix into the external environment. With the passage of time and continuous drug release, the delivery rate normally decreases in these types of systems since the bioactive agent has to traverse a long distance progressively and thereby require a longer diffusion time for ultimate delivery of drug(s).
The cumulative amount of drug released in this matrix type DDS can be expressed as:
Q = (A-Cp/2) p (1) Here, Q is cumulative amount of drug release
A is the initial amount of drug solids impregnated in a unit volume of polymer matrix.
Cp is the solubility of drug in polymer phase
p is thickness of hydrodynamic diffusion layer
Dissolution Controlled Monolithic-Matrix Delivery System
In this approach, drug is dispersed in a slow dissolving matrix consisted of polymer(s). The rate of penetration of the dissolution fluid into the matrix determines the drug dissolution and subsequent release. The penetration of dissolution fluid is however, dictated by the matrix, porosity, presence of hydrophobic additives and the wettability of system and surface of particle.
Figure 02: Dissolution controlled monolithic-matrix delivery system
Hydrogels-Matrix Drug Delivery System
Hydrogels are water-swollen three-dimensional network of hydrophilic homopolymers or copolymers. They are rendered insoluble because of chemical or physical cross-links. The physical cross-links include crystallites, entanglements or weak associations like hydrogen bonds or Vander Waal forces. These cross-links provide the physical integrity and network structure.
Hydrogels may exhibit swelling behavior dependent on the external environment. These hydrogels show drastic changes in their swelling ratio due to changes in their external pH, temperature, ionic strength, nature of the swelling agent, and electromagnetic radiations.
An advantage of hydrogels is that they may provide desirable protection from the potentially harsh environment in the vicinity of the release site.
Figure 03: Drug release from hydrogel based DDS
Hydrogels- the polymeric materials that can absorb a significant amount of water (>20% of its weight) while maintaining a distinct three dimensional structure.
Mode of Action of Hydrophilic Matrix Dosage Form (26, 27)
Hydrophilic matrix dosage forms essentially consist of a compressed blend of hydrophilic polymer and drug.
Tablet erosion :
Outer layer becomes fully hydrated, eventually dissolving into the gastric fluids.
Gel layer Ingestion of tablet
Initial wetting :
Tablet surface wets and polymer begins to hydrate,
Expansion of the gel layer :
Water permeates into the tablet, increasing the
Soluble drug:
Is released primarily by diffusion through the
Insoluble drug : Is released primarily
According to the generally accepted mechanism, the drug release from hydrophilic matrix dosage forms starts when the tablet comes in contact with gastrointestinal fluid. The surface of the tablet hydrates to release exposed drug and at the same time form a viscous polymer mucilage or gel. This gel fills the interstices within the tablet, retarding further ingress of liquid.
The concentration of polymer within the hydrated layer ranges from dilution at the outer surface to around 90% at the boundary with the drug core. Within this layer, drug in various states of dissolution (undissolved in dilute solution; in saturated solution) is distributed amongst the other ingredients of the tablets.
Drug release occurs immediately from the surface (burst effect) followed by diffusion through, and / or erosion of, the hydrated layer. The relative proportions of drug released by diffusion and erosion are determined by the drug’s solubility properties and by the physical and chemical nature of the hydrated polymer. This in turn is influenced by other factors, including drug characteristics, dissolution medium and other, which continue to be investigated.
Figure 04: Mode of action of hydrophilic matrix dosage form
Basic Kinetics of Controlled Drug Delivery28
In order to establish a basis for discussion of the influence of drug properties and the route of administration on controlled drug delivery, following mechanisms need a fair mention,
Behavior of drug within its delivery systems
Behavior of the drug and its delivery system jointly in the body.
The first of the two elements basically deal with the inherent properties of drug molecules, which influence its release from the delivery system. For conventional systems, the rate-limiting step in drug availability is usually absorption of drug across a biological membrane such as the gastro intestinal wall.
However, in sustained/controlled release product, the release of drug from the dosage form is the rate limiting instead, thus, drug availability is controlled by the kinetics of drug release than absorption.
Factors Influencing the In Vivo Performance of Sustained Release Dosage Formulations29
There are various factors that can influence the performance of a sustained release product. The physiological, biochemical, and pharmacological factors listed below can complicate the evaluation of the suitability of a sustained release dosage formulation.
Physiological
1. Prolonged drug absorption
2. Variability in GI emptying and motility 3. Gastrointestinal blood flow
4. Influence of feeding on drug absorption
Pharmacokinetic/ Biochemical 1. Dose dumping
2. First- pass metabolism
3. Variability in urinary pH; effect on drug elimination 4. Enzyme induction/ inhibition upon multiple dosing
Pharmacological 1. Changes in drug effect upon multiple dosing 2. Sensitization/ tolerance
Design and Fabrication of Oral Controlled Release Drug Delivery Systems (17, 22,
27, 30, 31)
The majority of the oral controlled release systems are either tablets or capsules although a few liquid products are also available. The paucity of liquid sustained release products is related to the nature of the sustained release mechanisms employed. Sustained release tablet and capsule dosage forms usually consist of two parts; an immediately available dose to establish the blood level quickly and a sustained part that contains several times the therapeutic dose for predicted drug levels.
The majority of oral controlled release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drug to the gastro intestinal tract. Starting with limited data on a drug candidate for sustained release, such as dose, rate constants for absorption and elimination, some elements of metabolism and some physical and chemical properties of the drug, one can estimate a desired release rate for the dosage form, the quantity of drug needed and a preliminary strategy for the dosage form to be utilized.
In Vitro Evaluation of Sustained Release Formulation
The data is generated in a well-designed reproducible in-vitro test such as dissolution test. The method should be sensitive enough for discriminating any change in formulation parameters and lot-to-lot variations. The key elements for dissolution are:
a) Reproducibility of method b) Proper choice of media
c) Maintenance of sink conditions d) Control of solution hydrodynamics
e) Dissolution rate as a function of pH ranging from pH 1 to 8 including several intermediate values preferably as topographic dissolution characterization.
Ideal in-vitro method can be utilized to characterize bio-availability of the sustained release product and can be relied upon to ensure lot-to-lot performance.
Drug Release Mechanism from Tablet Matrices
From time to time, various authors have proposed different types of drug release mechanism from matrices. It has been proposed that drug release from matrices usually implies water penetration in the matrix, hydration, swelling, diffusion of the dissolved drug (polymer hydro fusion), and/or the erosion of the gelatinous layer. Several kinetics models relating to the drug release from matrices are described below.10
Zero-order kinetics W = k1 t
First-order kinetics ln (100-W) = ln 100 – k2t
Hixon-Crowel’s cube-root equation (erosion model) (100 – W) 1/3 = 1001/3 – k3t
Higuchi’s square root of time equation (diffusion model) W = k4t1/2
Korsmeyer et al equation (release model) Qt / Q = K tn
Where W is percent drug release at time t and k1 to k4 are release rate constants, depending on the kinetic model used. The release mechanism of a drug would depend on the dosage form selected, pH, and nature of the drug and, of course, the polymer used.
Comparison of Dissolution Profiles
Comparison of therapeutic performances of two medicinal products containing the same active substance is a critical means of assessing the possibility of alternative using between the innovator and any essentially similar medicinal product.
The dissolution profile comparison may be carried out using model independent or model dependent method. A simple model independent approach
uses a difference factor (f1) and a similarity factor (f2) to compare dissolution profiles.32
Matrix tablets for the last two decades have been popular in the formulation of controlled release.
St=1n
(Rt-Tt)
f1 = x 100 St=1nRt
f2 = 50 x log {[1+ (1/n) St=1n(Rt– Tt) 2]-0.5 x 100}
Where, Rtand Tt represent the average percent dissolved at time t for reference and test, respectively, and n is the number of time points tested.
Dissolution profile was considered satisfactory if f1 values lies below 50 (nearing zero) and f2 value lies more than 50 (nearing 100).
The model independent method is most suitable for dissolution profile comparison when three to four or more dissolution time points are available.
Matrix tablets for the last two decades have been popular in the formulation of controlled release.
Table 04:Various drugs formulated as sustained release matrix tablets using different techniques
Drug Technique Year
Ambroxol HCl33 Direct Wet granulation 2007
Diclofenac sodium34 Direct compression 2006
Cefpodoxime35 Direct compression 2006
Dextromethorphan Resinate36 Direct compression 2005
Tramadol HCl37 Direct compression 2005
Zidovudine38 Wet granulation 2005
Carbamazepine39 Direct compression 2004
As listed inTable 4, different methods are used to prepare matrix tablets i.e.
direct compression, wet granulation, melt dispersion and Fluid bed granulation. But in sustained release technology, directly compressed matrix tablets are the most attractive both scientifically and economically.
Hypertension
Hypertension, also referred to as high blood pressure, is a medical condition in which the blood pressure is chronically elevated. Hypertension can be classified either as essential (primary) or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. Secondary hypertension indicates that the high blood pressure is a result of (i.e., secondary to) another condition, such as kidney disease or tumours (pheochromocytoma and paraganglioma).12
Alpha Blockers
Niacin23 Direct compression 2004
Metformin HCl40
Wet granulation
2004
Lithium carbonate41 Direct compression 2004
Nicorandil42 Wet granulation 2003
Aspirin43 Direct compression 2001
Metoclopramide HCl16 Melt dispersion 2002
Ketoprofen44 Fluid bed granulation 2002
Isosorbide dinitrate45 Direct compression 2001 Prochlorperazine maleate3 Direct compression 2000
Theophylline46 Direct compression 1998
Medications that bind alpha adrenergic receptors and decrease the workload of the heart and lower blood pressure are known as alpha blockers. They are commonly used to treat hypertension, peripheral vascular disease, and hyperplasia.
Alpha1-adrenergic blockers are drugs that work by blocking the alpha1- receptors of vascular smooth muscle, thus preventing the uptake of catecholamines by the smooth muscle cells. This causes vasodilation and allows blood to flow more easily.
These drugs, like alpha blockers are used for two main purposes to treat hypertension and to treat benign prostatic hyperplasia, a condition that affects men and is characterized by an enlarged prostate gland.
Commonly prescribed alpha blockers for hypertension and benign prostatic hyperplasia include doxazosin (Cardura), prazosin (Minipress) and terazosin (Hytrin). Prazosin is also used in the treatment of congestive heart failure.13
2. LITERATURE REVIEW
Jaleh V et al.,37 developed a Tramadol HydrochlorideMatrix Tablets. In vitro release of the matrix tablets were subjected to the paddle dissolution method using 900 mL of phosphate buffer solution pH 7.4 ± 0.2 as the dissolution medium. The dissolution test was performed at 100 rpm and the temperature was set at 37°C ± 1°C.
Reddy et al.,42 developed once daily sustained release tablets of nicorandil.
The USP-24 dissolution apparatus type II at rotation speed 75 rpm. The dissolution medium consisted of 0.1N HCl for the first 2 hours and the phosphate buffer pH 7.4 from 3 to 24 hours (900 ml), maintained at 37 +0.5oC.
Munishet al., developed an matrix tablet of verapamil hydrochloride. The in vitro drug release studies were carried out using USP type 2 dissolution apparatus, at 37± 0.50C and paddle speed of 50 rpm in buffer of pH 1.2 and pH 6.8 for first 2 hours and next 8 hours respectively.
Xiaochenet al.,28 developed an matrix tablet of acrivastine and psudoephedrine. The in vitro release was carried out in distilled water using USP I apparatus at 50 rpm.
P. G. Yeoleet al.,34Design and evaluation of xanthan gum-based sustained release matrix tablets of diclofenac sodium. In vitro drug release was studied using USP I apparatus,with 900 ml of dissolution medium maintained at 37±1° for 12 h, at 50 rpm. 0.1 N HCl (pH 1.2) was used as a dissolution medium for the first 2 h, followed by pH 6.8 phosphate buffer for further 10 h.
Vaithiyalingamet al.,44 developed a ketoprofen sustained release tablets. In vitro release was carried out in a USP type II paddle, dissolution test apparatus at 50 rpm. Operating condition
Hosseinaliet al.,47 developed a sustained release matrix tablet of aspirin. The in vitro release was carried out in a USP type II dissolution apparatus at 30 rpm.
Dissolution medium was 1000 ml distilled water maintained at 37 +0.5oC.
Paradkaret al.,40 developed sustained release matrices of metformin HCl. The in vitro release was carried out in a USP 24 type II dissolution apparatus with a stirring rate of 100 rpm. Dissolution medium was 900 ml highly purified water maintained at 37 +0.5oC.
Kale et al., developed matrix tablet of metformin HCl. the USP-23 dissolution apparatus type I (basket) at rotation speed of 75 rpm was used for in vitro dissolution drug release testing. The dissolution medium consisted of 900 ml of distilled water at 37 +0.5oC.
Derle DV et al.26developed a sustained release system for ambroxol hydrochloride from guar gum by using various concentration of polymer in order to achieve theoretical drug release profile. All the sustained release matrix formulations were evaluated for physical tests, swelling behavior, stability studies and in vitro drug release rate.
3. AIM AND OBJECTIVE
The main objective behind present study is to develop oral sustained release formulations based on hydrophilic monolithic matrices-hydrogels drug delivery system which provides therapy for the treatment of hypertension.
The main objectives of the present investigation are:
1. To develop a suitable sustained release matrix tablets of prazosin hydrochloride using different polymers.
2. Evaluation of drug loaded matrix tablets for physical and chemical parameters.
3. To decrease the size and cost of the tablet when compared to the existing marketed products so as to facilitate the patients.
4. In vitro evaluation and comparison of matrix tablets with marketed product.
In the present studies, efforts were made to develop a sustained release formulation of prazosin hydrochloride for treatment of hypertension. The intended formulation was matrix tablet of prazosin hydrochloride, which will provide similar in vitro release profile to that of commercial marketed products by calculating f1
(difference factor) and f2 (similarity factor).
Prazosin hydrochloride is available in the market as an extended release dosage form tablets in the form of osmotic pump system, which requires sophisticated facilities for the manufacture, complexity of the process, large quantity of excipients, and altogether making the formulation costly. So it was challenge to develop matrix tablets using simpler methods and cheaper excipients, which altogether reduces the cost of the tablets.
PRAZOSIN HYDROCHLORIDE
Prazosin hydrochloride is an alpha-adrenergic blocking agent, which is effectively used in the treatment of hypertension and benign prostatic hyperplasia.
Accordingly, Prazosin hydrochloride is a selective inhibitor of the alpha 1 subtype of alpha adrenergic receptors. Studies in normal human subjects have shown that
phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine.14 It is excreted unchanged in the urine and does not undergo hepatic metabolism. It has a half-life of 2-3 hours. Its daily oral dose is 20 mg/day in divided doses.
RATIONALE FOR DRUG SELECTION
1. Absorption of the prazosin hydrochloride is in the GI tract and its bioavailability is 50-85%. Hence prazosin hydrochloride is suitable for matrix drug delivery system.
2. Size of marketed prazosin hydrochloride sustained release tablets is high.
Therefore size can be decreased by preparing prazosin hydrochloride matrix tablets using less excipient.
3. As the dose of prazosin hydrochloride is 5 mg (marketed formulations is available in 2.5 mg and 5 mg tablets) so it is suitable for sustained release dosage form.
4. Prazosin hydrochloride has a biological half-life of 2-3 hours. Hence, it requires 2-3 times a day dosing.
Thus prazosin hydrochloride is suitable drug candidate for developing sustained release dosage form.
In view of these objectives, an extensive literature search was done and the important aspects were highlighted in the next chapter, “Literature Review”
4.PLAN OF WORK
1. Preformulation Study
Organoleptic properties
Solubility
Determination of melting point
Compressibility index
PH
Loss on drying 2. Evaluation of Powders
Angle of repose
Bulk density
Tapped density
Powder flow Properties
3. Compression of powders into tablet 4. Tablet evaluation
Thickness
Hardness
Friability
Uniformity of weight
Drug content
Tablet density
In vitro buoyancy studies
In vitro dissolution 5. Kinetic Studies
5. DRUG PROFILE& EXCIPIENTS PROFILE
5.1 DRUG PROFILE
Prazosin Hydrochloride
(14, 48, 49, 50, 51, 55)Introduction:
Prazosin hydrochloride is an alpha-adrenergic blocking agent used to treat hypertension and benign prostatic hyperplasia. Accordingly, Prazosin hydrochloride is a selective inhibitor of the alpha1 subtype of alpha adrenergic receptors. Prazosin hydrochloride, a quinazoline derivative, is the first of a new chemical class of antihypertensives. It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is:
Structure:
Chemical Name : [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin- 1-yl]-furan-2-ylmethanone
Empirical Formula : C19H21N5O4 Molecular Weight : 419.87 g/mol Melting Point : 279 oC
Category : Antihypertensive Agents, Adrenergic alpha- Antagonists
Dose : 20 mg/day in two-three divided doses Water Solubility : 0.2 mg/mL (as HCl salt)
Description : white powder, odourless.
Solubility : very slightly soluble in water (0.2 mg/ml as HCl salt) and soluble in methanol (6 mg/ml), ethanol, dimethyl
formamide, and dimethyl acetamide.
Storage : Store in a well-closed, light-resistant container Pharmacokinetics
Absorption
Well-absorbed from gastrointestinal tract; bioavailability is variable (50 to 85%).
Distribution
The apparent volume of distribution (Vd) of prazosin hydrochloride is 0.60 + 0.13 L/kg. It is widely distributed throughout the plasma, tissue, liver, kidney and the lowest in brain and reaches to most tissues and body fluids like blood serum and bile.
Metabolism-Primarily hepatic. Several metabolites have been identified in humans and animals (6-O-demethyl, 7-O-demethyl, 2-[1-piperazinyl]-4-amino-6, 7- dimethoxyquinazoline, 2, 4-diamino-6, 7-dimethoxyquinazoline); in dog studies, three of the metabolites were shown to be responsible for approximately 10 to 25%
of prazosin hydrochloride hydrochloride's hypotensive activity.
Elimination
Primarily in bile and feces; 6 to 10% in urine.Excreted as unchanged drug (5 to 11%) and metabolites. Elimination of prazosin hydrochloride may be slower in patients with congestive heart failure than in normal subjects.
Mechanism of Action
Prazosin hydrochloride is a selective alpha 1 -adrenergic blocking agent. The
Hypertension
Prazosin hydrochloride produces vasodilation and reduces peripheral resistance but generally has little effect on cardiac output. Antihypertensive effect is usually not accompanied by reflex tachycardia. There is little or no effect on renal blood flow or glomerular filtration rate.
Congestive Heart Failure
Beneficial effects, resulting from vasodilation, are due to decreased systemic resistance, preload and after load reduction, and resulting in improved cardiac output.
Raynaud's Phenomenon-Therapeutic effect for vasospasm is due to inhibition of vasoconstriction by blocking of postsynaptic alpha 1 receptors.
Benign Prostatic Hyperplasia
Relaxation of smooth muscle in the bladder neck, prostate, and prostate capsule produced by alpha 1 -adrenergic blockade results in reduction of urethral resistance and pressure, bladder outlet resistance, and urinary symptoms.
Indications Hypertension
Prazosin hydrochloride is indicated in the treatment of hypertension.
Congestive Heart Failure
Prazosin hydrochloride may be used as an adjunct to digoxin and diuretics for the treatment of congestive heart failure. However, prazosin hydrochloride has not been shown to improve survival in these patients.
Toxicity, Ergot Alkaloid
Prazosin hydrochloride is used for treatment of peripheral vasospasm caused by ergot alkaloid overdose.
Pheochromocytoma
Prazosin hydrochloride is used for the management of hypertension associated with pheochromocytoma.
Raynaud’s Phenomenon
Prazosin hydrochloride is used for treatment of Raynaud’s phenomenon.
Benign Prostatic Hyperplasia (BPH)
Prazosin hydrochloride is used for the treatment of urinary symptoms associated with benign prostatic hyperplasia. Prazosin hydrochloride has been shown to improve urinary flow and symptoms of BPH. However, the long-term effects of prazosin hydrochloride on the incidence of acute urinary obstruction or other complications of BPH or on the need for surgery have not yet been determined.
Dosage and Administration
The dose of prazosin hydrochloride in children:
Initially 5 mg/kg/dose every 6 hours; increase dosage gradually up to maximum of 25 mg/kg/dose every 6 hours.
The dose of prazosin hydrochloride in adults:
Hypertension: Initially 1 mg/dose 2-3 times/day; usual maintenance dose: 3-15 mg/day in divided doses 2-4 times/day; maximum daily dose: 20 mg
Hypertensive urgency: 10-20 mg once, may repeat in 30 minutes Raynaud's phenomenon: 0.5-3 mg twice daily
Benign prostatic hyperplasia: 2 mg twice daily.
When adding a diuretic or other antihypertensive agent, the dose of Prazosin hydrochloride should be reduced to 1 mg or 2 mg three times a day and retitration then carried out.
It is commercially available in 1 mg, 2mg and 5 mg conventional tablet and 2.5 mg, 5mg extended release tablet.
Contraindications
Prazosin hydrochloride is contraindicated in patients with known allergy to the quinazolines group of medicines.
Concurrent use of prazosin hydrochloride antagonizes the peripheral
Concurrent use of prazosin hydrochloride may block the alpha-adrenergic effects of epinephrine, possibly resulting in severe hypotension and tachycardia.
Concurrent use with phosphodiesterase-5 (PDE-5) inhibitors including sildenafil (>25 mg), tadalafil, or vardenafil.
Adverse Effects
“first-dose orthostatic hypotensive reaction” sometimes occurs, most frequently 30 to 90 minutes after the initial dose of prazosin hydrochloride, and may be severe. Syncope or other postural symptoms, such as dizziness, may occur.
Subsequent occurrence with increase dosage is also possible. Incidence appears to be dose-related; thus, it is important that therapy be initiated with the lowest possible dose. Patients who are volume-depleted or sodium-restricted may be more sensitive to the orthostatic hypotensive effects of prazosin hydrochloride, and the effect may be exaggerated after exercise. Hypotensive side effects may be more likely to occur in geriatric patients.
The following adverse effects have been selected on the basis of their potential clinical significance:
Those Indicating Need for Medical Attention Incidence More Frequent
Dizziness and orthostatic hypotension Incidence Less Frequent Edema (swelling of feet or lower legs)
palpitations (pounding heartbeat)
urinary incontinence (loss of bladder control) Incidence Rare
Angina (chest pain)
dyspnea (shortness of breath)
priapism (painful, inappropriate erection of the penis)
Those Indicating Need for Medical Attention Only if They Continue
Incidence More Frequent
Drowsiness and Headache
Malaise (lack of energy) Incidence Less Frequent
Dryness of mouth and nervousness
fatigue (unusual tiredness or weakness) Incidence Rare
Nausea
urinary frequency (frequent urge to urinate)
5.2. POLYMER REVIEW
5.2.1
Hydroxypropyl Methylcellulose (HPMC)
52Synonyms: Cellulose, hydroxypropyl methyl ether, methocel, metolose, and pharmacoat.
Structure:
Empirical Formula:
HPMC is a partially o-methylated and o-(2-hydroxypropylated) cellulose. It is available in several grades, which vary in viscosity and extent of substitution.
Molecular Weight: 10 000 – 1 500 000
Description: HPMC is an odorless and taste less, white or creamy white colored fibrous or granular powder.
Functional Category: Coating agent, film-former, stabilizing agent, suspending agent, tablet binder, viscosity-increasing agent
Applications in Pharmaceutical Formulation:
HPMC is widely used in oral and topical pharmaceutical formulations. In oral product it is primarily used as a tablet binder and as an extended release tablet matrix. Concentration of between 2-5% w/w may be used as a binder either in wet or in dry granulation process. High viscosity grades may be used to retard the release of water-soluble drug from a matrix.
Solubility: Soluble in cold water, forming a viscous colloidal solution.Practically insoluble in chloroform, ethanol, and ether, but soluble in mixture of ethanol and dichloromethane, and mixture of methanol and dichloromethane.
Stability and Storage Conditions:
HPMC is a stable material although it is hygroscopic after drying. Solutions are stable between pH 3-11. Increasing temperature reduces the viscosity of solutions. It undergoes a reversible sol to gel transformation upon heating and cooling respectively. HPMC powder should be stored in a well-closed container, in a cool, dry place.
