FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS.
A Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI- 600 032
In partial fulfilment of the award of the degree of
MASTER OF PHARMACY IN
Branch-I -- PHARMACEUTICS
Submitted by
Name: MUTHUMAHARAJA M REG.No.261810256
Under the Guidance of Mr. K. JAGANATHAN, M.Pharm.,
ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACEUTICS
J.K.K. NATTARAJA COLLEGE OF PHARMACY KUMARAPALAYAM – 638183
TAMILNADU.
FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS.
A Dissertation submitted to
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI - 600 032
In partial fulfilment of the award of the degree of
MASTER OF PHARMACY IN
Branch-I -- PHARMACEUTICS Submitted by
Name: MUTHUMAHARAJA M REG.No.261810256
Under the Guidance of Mr. K. JAGANATHAN, M.Pharm.,
ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACEUTICS
J.K.K. NATTARAJA COLLEGE OF PHARMACY KUMARAPALAYAM – 638183
TAMILNADU.
CERTIFICATES
This is to certify that the dissertation work entitled
“FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID)
FLOATING TABLETS”, submitted by the student bearing REG.No.261810256 to “The Tamil Nadu Dr. M.G.R. Medical University – Chennai”, in partial fulfilment for the award of Degree of Master of Pharmacy in
Pharmaceutics was evaluated by us during the examination held on………..……….
Internal Examiner External Examiner EVALUATION CERTIFICATE
This is to certify that the work embodied in this dissertation entitled
“FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS”, submitted to “The Tamil Nadu Dr. M.G.R. Medical University- Chennai”, in partial fulfilment and requirement of university rules and regulation for the award of Degree of Master of Pharmacy in Pharmaceutics, is a bonafide work carried out by the student bearing
REG.No.261810256 during the academic year 2019-2020, under the guidance and supervision of Mr. K.JAGANATHAN, M.Pharm., Associate Professor, Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy,
Kumarapalayam.
CERTIFICATE
Dr. R. Sambathkumar, M. Pharm., PhD., Professor & Principal,
Dr. S. Bhama, M. Pharm., PhD., Professor & HOD,
Department of Pharmaceutics Mr. K.Jaganathan, M.Pharm.,
Associate Professor,
Department of Pharmaceutics
This is to certify that the work embodied in this dissertation
entitled “FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS”, submitted to “The Tamil Nadu Dr. M.G.R. Medical University - Chennai”, in partial fulfilment and requirement of university rules and regulation for the award of Degree of Master of Pharmacy in Pharmaceutics, is a bonafide work carried out by the student bearing
REG.No.261810256 during the academic year 2019-2020, under my guidance and d i re ct supervision in the Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
Place: Kumarapalayam Date:
CERTIFICATE
Mr. K. Jaganathan, M.Pharm., Associate Professor,
Department of Pharmaceutics
This is to certify that the work embodied in this dissertation
entitled “FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS”, submitted to “The Tamil Nadu Dr. M.G.R. Medical University- Chennai”, in partial fulfilment and requirement of university rules and regulation for the award of Degree of Master of Pharmacy in Pharmaceutics, is a bonafide work carried out by the student bearing
REG.No.261810256 during the academic year 2019-2020, under the guidance and supervision of Mr. K.Jaganathan, M.Pharm., Associate Professor,
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
Place: Kumarapalayam Date:
CERTIFICATE
Dr. R. Sambathkumar, M. Pharm., PhD., Professor & Principal,
J.K.K.Nattraja College of Pharmacy, Kumarapalayam.
DECLARATON
I do hereby declared that the dissertation “FORMULATION AND INVITRO EVALUATION OF ACECLOFENAC (NSAID) FLOATING TABLETS”, submitted to
“The Tamil Nadu Dr. M.G.R Medical University - Chennai”, for the partial fulfilment of the degree of Master of Pharmacy in Pharmaceutics, is a bonafide research work has been carried out by me during the academic year 2019-2020, under the guidance and supervision of Mr. K. Jaganathan, M.Pharm., Associate Professor, Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam.
I further declare that this work is original and this dissertation has not been submitted previously for the award of any other degree, diploma,
associate ship and fellowship or any other similar title. The information furnished in this dissertation is genuine to the best of my knowledge.
Place: Kumarapalayam MUTHUMAHARAJA M
Date: REG.No.261810256
Dedicated to Parents, Teachers&
My Family
ACKNOWLEDGEMENT
ACKNOWLEDGEMENT
I am proud to dedicate my deep sense of gratitude to the founder, (Late) Thiru J.K.K. Nattaraja Chettiar, providing the historical institution to study.
My sincere thanks and respectful regards to our reverent Chairperson Smt. N. Sendamaraai, B.Com., and Director Mr. S. Omm Sharravana, B.Com., LLB., J.K.K. Nattraja Educational Institutions, Kumarapalayam for their blessings, encouragement and support at all times.
It is most pleasant duty to thank for our beloved Dr. R. Sambathkumar, M.Pharm., Ph.D., Principal & Professor,
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam for ensuring all the facilities were made available to me for the smooth running of this project and 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.
It is my privilege to express deepest sense of gratitude toward Mr. K.Jaganathan, M.Pharm., Associate Professor, Department of Pharmaceutics, for their valuable suggestions and inspiration.
Our glorious acknowledgement to our administrative officer Dr. K. Sengodan, M.B.B.S., for encouraging using kind and generous manner to complete this work.
My sincere thanks to Dr. S. Bhama, M. Pharm., Ph.D., Professor & HOD, Department of Pharmaceutics, Mr. R. Kanagasabai, B.Pharm, M.Tech., Associate Professor, Dr. V. Kamalakannan M.
Pharm., Ph.D., Associate Professor, Mr. c. Kannan, M.Pharm., Assistant Professor, Ms. S. Manodhini Elakkiya, M.Pharm., Lecturer, Mr. M. Subramani, M.Pharm., Lecturer and Dr. Rosmi Jose,
Professor and Head, Department of Pharmacy Practice,
Mrs. K. Krishna Veni, M.Pharm., Assistant Professor, Mr. R.
Kameswaran M.Pharm, Assistant Professor, Dr. Mebin Alias, Pharm.D., Assistant Professor, Mrs. P. J. Sujitha, Lecturer, Dr. Cindy Jose, Pharm.D., Lecturer, Dr. Krishna Ravi, Pharm.D., Lecturer, and Dr. S.K.Sumitha, Pharm.D., Lecturer, Department of Pharmacy Practice, for their help during my project.
It is my privilege to express deepest sense of gratitude toward Dr. M. Vijayabaskaran, M.Pharm., Ph.D., Professor & Head, Department of Pharmaceutical chemistry, Mrs. B. Vasuki, M.Pharm., Assistant Professor and Ms. P. Lekha, Lecturer for their valuable suggestions and inspiration.
My sincere thanks to Dr. V. Sekar, M.Pharm., Ph.D., Professor and Head, Department of Analysis, Dr. I. Caolin Nimila, M.Pharm., Ph.D., Assistant Professor, Mr. D. Kamalakannan Assistant Professor, Mrs. P. Devi, M.Pharm., Lecturer and Ms. V. Devi, M.Pharm., Lecturer, Department of Pharmaceutical Analysis for their valuable suggestions.
My sincere thanks to Dr. Senthilraja, M.Pharm., Ph.D., Associate Professor and Head, Department of Pharmacognosy, Mrs. P.Meena Prabha, M.Pharm., Lecturer, Department of Pharmacognosy and Mr. Nikhil.P.S, M.Pharm., Lecturer, Department of Pharmacognosy for their valuable suggestions during my project work.
My sincere thanks to Dr. R. Shanmugasundaram, M.Pharm., Ph.D., Vice Principal & HOD, Department of Pharmacology,
Dr. C. Kalaiyarasi, M.Pharm., Ph.D., Associate Professor, Mr.
V. Venkateswaran, M.Pharm., Assistant Professor, Mrs. M. Sudha M.Pharm., Lecturer, Mr. T. Thiyagarajan, M.Pharm., Assistant Professor, Mrs. R. Elavarasi, M.Pharm., Lecturer, Mrs. M. Babykala, M.Pharm., Lecturer, and Mrs. P.J. Sujitha, M.Pharm., Lecturer, Department of Pharmacology for their valuable suggestions during my project work.
I greatly acknowledge the help rendered by Mrs. K. Rani, Office Superintendent,Miss. S. Sudhalakshmi, Typist, Mrs. V. Gandhimathi, M.A., M.L.I.S., Librarian, Mrs. S. Jayakala B.A., B.L.I.S., and Asst. Librarian for their co-operation. I owe my 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.
MUTHUMAHARAJA M
REG.No.261810256
CHAPTER 1
INTRODUCTION
CHAPTER 2
LITERATURE REVIEW
CHAPTER 3
DRUG AND EXCIPIENT
PROFILE
CHAPTER 4
AIM AND OBJECTIVE
CHAPTER 5
PLAN OF WORK
CHAPTER 6
MATERIALS AND
METHODS
CHAPTER 7
RESULTS AND
DISCUSSION
CHAPTER 8
SUMMARY AND
CONCLUSION
CHAPER 9
BIBILOGRAPHY
CONTENTS
S Nos. Chapters Page No.
1. Introduction 1-12
2. Review of Literature 13-23
3. Drug and excipient profile 24-35
4. Aim and Objectives 36-37
5.
6.
7.
8.
Plan of work
Material and Methods
Results and Discussion
Summary And Conclusion
38 39-48
49-97
98
9. Bibliography 99-105
Introduction
1. INTRODUCTION1, 2, 3 1.1 GASTRORETENTIVE DRUG DELIVERY SYSTEM
The oral route is considered as the most promising route of drug delivery.
Effective oral drug delivery may depend upon the factors such as gastric emptying process, gastrointestinal transit time of dosage form, drug release from the dosage form and site of absorption of drugs. Most of the oral dosage forms possess several physiological limitations such as variable gastrointestinal transit, because of variable gastric emptying leading to non-uniform absorption profiles, incomplete drug release and shorter residence time of the dosage form in the stomach. This leads to incomplete absorption of drugs having absorption window especially in the upper part of the small intestine, as once the drug passes down the absorption site, the remaining quantity goes unabsorbed. The gastric emptying of dosage forms in humans is affected by several factors because of which wide inter- and intra-subject variations are observed 1. Since many drugs are well absorbed in the upper part of the gastrointestinal tract, such high variability may lead to non-uniform absorption and makes the bioavailability unpredictable. Hence, a beneficial delivery system would be one which possesses the ability to control and prolong the gastric emptying time and can deliver drugs in higher concentrations to the absorption site (i.e. upper part of the small intestine).
The identification of new diseases and the resistance shown towards the existing drugs called for the introduction of new therapeutic molecules. In response, a large number of chemical entities have been introduced, of which some have absorption all over the gastrointestinal tract (GIT), some have absorption windows (i.e. absorption sites), especially the upper part of the small intestine and some drugs have poor solubility in intestinal media. The drugs belonging to the second and third categories, and the drugs which are required for local action in the stomach, require a specialized delivery system. All the above requirements can be met and effective delivery of the drugs to the absorption window, for local action and for the treatment of gastric disorders such as gastro-esophageal reflux, can be achieved by floating drug delivery systems (FDDS).
To date, a number of FDDS involving various technologies, carrying their own advantages and limitations were developed such as, single and multiple unit hydro dynamically balanced systems (HBS), single and multiple unit gas generating systems, hollow microspheres and raft forming systems2.
The hydrodynamic balanced system (HBS) also called Floating drug delivery system (FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time of the dosage form within the GIT. HBS is a formulation of a drug with gel forming hydrocolloids meant to remain buoyant in the stomach contents.
Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions3.
The retentive characteristics of the dosage form are not significant for the drugs that:
1) Are insoluble in intestinal fluids 2) Act locally
3) Exhibit site-specific absorption.
However, the system can be used for most of the drugs, where controlled (sustained) release of the dosage form is desired by the oral route.
The formulation of the dosage form must comply with three major criteria for HBS.
1) It must have sufficient structure to form a cohesive gel barrier.
2) It must maintain an overall specific gravity less than that of gastric content.
3) It should dissolve slowly enough to serve as a “Reservoir” for the delivery system.
Floating systems are one of the important categories of drug delivery systems with gastric retentive behavior. Drugs that could take advantage of gastric retention include: furosemide, cyclosporine, allopurinol ciprofloxacin and metformin. Drugs whose solubility is less in the higher pH of the small intestine than the stomach (e.g.
chlordiazepoxide and cinnarizine, the drugs prone for degradation in the intestinal pH (e.g. captopril), and the drugs for local action in the stomach (e.g. misoprostol) can be
Introduction
delivered in the form of dosage forms with gastric retention. Antibiotics, catecholamines, sedative, analgesics, anticonvulsants, muscle relaxants, antihypertensive and vitamins can be administered in HBS dosage form.4, 5,6,7,8
Drugs reported to be used in the formulation of floating dosage forms are:
Floating microspheres (aspirin, griseofulvin, p-nitroaniline, aceclofenac, terfinadine and tranilast), floating granules (diclofenac sodium, indomethacin and prednisolone), films (cinnarizine), floating capsules (chlordiazepoxide hydrogen chloride,diazepam, furosemide, misoprostol, L-Dopa, benserazide, ursodeoxycholic acid and pepstatin) and floating tablets and pills (acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, para aminobenzoic acid, piretamide, theophylline and verapimil hydrochloride, etc.).
Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.
1.2 ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEM7,8,21,22
Gastro retentive drug delivery systems have numerous advantages listed below:
1) The principle of HBS can be used for any particular medicament or class of medicament.
2) HBS formulations are not restricted to medicaments, which are principally absorbed from the stomach. Since it has been found that these are equally efficacious with medicaments which are absorbed from the intestine e.g.
Chlorpheniramine maleate.
3) The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids.
4) The efficacy of the medicaments administered utilizing the sustained release
principle of HBS has been found to be independent of the site of absorption of the particular medicaments.
5) Administration of a prolonged release floating dosage form tablet or capsule will result in dissolution of the drug in gastric fluid. After emptying of the stomach contents, the dissolved drug will be available for absorption in the small intestine.
It is therefore expected that a drug will be fully absorbed from the floating dosage form if it remains in solution form even at alkaline pH of the intestine.
6) When there is vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, poor absorption is expected under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.
7) Gastric retention will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.
8) Many drugs categorized as once-a-day delivery have been demonstrated to have suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended release development challenging. Therefore, a system designed for longer gastric retention will extend the time within which drug absorption can occur in the small intestine.
9) Certain types of drugs can benefit from using gastro retentive devices. These include:
• Drugs acting locally in the stomach;
• Drugs those are primarily absorbed in the stomach;
• Drugs those are poorly soluble at an alkaline pH;
• Drugs with a narrow window of absorption;
• Drugs absorbed rapidly from the GI tract; and • Drugs those degrade in the colon.
Introduction
1.3 DISADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS
1) The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bio-adhesive polymers that easily adhere to the mucosal lining of the stomach.
2) Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment should not be formulated in gastro retentive systems.
3) Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric retention system.
1.4 APPROACHES TO GASTRIC RETENTION 9, 10, 11,12,13,14
Several approaches have been attempted in the preparation of gastro-retentive drug delivery systems. These include floating systems, swellable and expandable systems, high density systems, bioadhesive systems, altered shape systems, gel forming solution or suspension systems and sachet systems.
Various approaches have been followed to encourage gastric retention of an oral dosage form. Floating systems have low bulk density so that they can float on the gastric juice in the stomach. The problem arises when the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to float on. Floating systems can be based on the following:
a. Hydro dynamically balanced systems (HBS)
Incorporated buoyant materials enable the device to float.
b. Effervescent systems
Gas-generating materials such as sodium bicarbonates or other carbonate salts are incorporated. These materials react with gastric acid and produce carbon dioxide, which entraps in the colloidal matrix and allows them to float.
c. Low-density systems
Have a density lower than that of the gastric fluid so they are buoyant.
d. Bioadhesive or mucoadhesive systems
These systems permit a given drug delivery system (DDS) to be incorporated with bio/mucoadhesive agents, enabling the device to adhere to the stomach (or other GI region) walls, thus resisting gastric emptying. However, the mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.
e. High-density Systems
Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach near the pyloric region, which is the part of the organ with the lowest position in an upright posture.
Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on diameter of the pellets, although many conflicting reports stating otherwise also abound in literature.
Commonly used Excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by upto 1.5–2.4 g/cm3. However, no successful high density system has made it to the market.
f. Large Single- unit Dosage Forms
These dosage forms are larger than the pyloric opening and so are retained in the stomach. There are some drawbacks associated with this approach. Permanent retention of rigid large-sized single-unit forms can cause bowel obstruction, intestinal adhesion and gastroplasty.
g. Co-administration of gastric- emptying delaying drugs
This concept of simultaneous administration of a drug to delay gastric emptying together with a therapeutic drug has not received the favour of clinicians
Introduction
and regulatory agencies because of the questionable benefit-to-risk ratio associated with these devices.
The stomach is a size-filtering system and so it would seem ideally suited to retaining a DDS that is larger than the pylorus. The drawback is that the DDS is not small enough to be taken orally if sizes larger than the pylorus are required. Several systems have been investigated to encourage gastric retention using increasing size of DDS. Systems have been based on expansion due to gases and swelling due to intake of external liquids.
h. Raft systems incorporate alginate gels
These have a carbonate component and, upon reaction with gastric acid, bubbles form in the gel, enabling floating of raft on gastric fluid.
1.5 METHODS FOR PREPARING FLOATING DOSAGE FORM 11,12,21,22
Following approaches can be used for preparing floating dosage forms:
(1) Using gel forming hydrocolloids such as hydrophilic gums, gelatin, alginates, cellulose derivatives, etc.
(2) Using low density enteric materials such as methacrylic polymer, cellulose acetate phthalate.
(3) By reducing particle size and filling it in a capsule.
(4) By forming carbon dioxide gas and subsequent entrapment of it in the gel network.
(5) By preparing hollow micro-balloons of drug using acrylic polymer and filled in capsules.
(6) By incorporation of inflatable chamber which contained in a liquid.
The factors which govern the effectiveness of active medicaments in HBS are:
1) Amounts of active medicament to produce therapeutic effect.
2) Bulk density.
3) Hydrophilic and hydrophobic properties.
4) Stability in gastric fluids.
Fig. 1.1 is showing the floating drug delivery in stomach
Fig.1.2 Mechanism of Floating Drug Delivery System
1.6 FACTORS AFFECTING GASTRORETENTIVE SYSTEM11, 12,13,14,15
Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include use of floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying
Introduction
devices and co-administration of gastric-emptying delaying drugs. Most of these approaches are influenced by a number of factors that affect their bioavailability and efficacy of the gastro retentive system.
Density – gastric retention time (GRT) is a function of dosage form buoyancy that is dependent on the density.
Size – dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared to those with a diameter of 9.9 mm.
Shape of dosage form – tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes.
Single or multiple unit formulation – multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to failure of units, allow co-administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.
Fed or unfed state – under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach and, if the timing of administration of the formulation coincides with that of the MMC, the GRT of the unit can be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.
Nature of meal – feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.
Caloric content – GRT can be increased by four to 10 hours with a meal that is high in proteins and fats.
Frequency of feed – the GRT can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.
Gender – mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface).
Age – elderly people, especially those over 70, have a significantly longer GRT.
Posture – GRT can vary between supine and upright ambulatory states of the patient.
Concomitant drug administration – anti cholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time.
Biological factors – diabetes and Crohn’s disease, etc.
1.7 LIMITATIONS 1
1) The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bioadhesive polymers that easily adhere to the mucosal lining of the stomach.
2) Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids.
3) The dosage form should be administered with a minimum of glass full of water (200-250 ml).
4) The drugs, which are absorbed throughout gastro-intestinal tract, which under go first-pass metabolism (nifedipine, propranolol etc.), are not desirable candidate.
5) Some drugs present in the floating system causes irritation to gastric mucosa.
Introduction
1.8 MARKETED PRODUCTS OF GRDDS
Some of the marketed formulations are listed as follows: 14,16,17,18
Table 1.1 Marketed Products of GRDDS
Brand name Delivery system Drug (dose) Company name
Valrelease® Floating capsule Diazepam (15mg) Hoffmann- LaRoche, USA Madopar® HBS
(Prolopa® HBS)
Floating, CR capsule Benserazide (25mg) and L-Dopa (100mg)
Roche Products, USA
Liquid Gaviscon®
Effervescent Floating liquid alginate preparations
Al hydroxide (95 mg), Mg Carbonate (358 mg)
GlaxoSmithkline, India
Topalkan® Floating liquid
alginate preparation
Al – Mg antacid Pierre Fabre Drug, France
Almagate Flot coat®
Floating dosage form Al – Mg antacid ---
Conviron® Colloidal gel forming FDDS
Ferrous sulphate Ranbaxy, India
1.9 APPLICATIONS AND TECHNOLOGIES 13, 14, 19, 20
1) Recent study indicated that the administration of diltiazem floating tablet twice a day might be more effective compared to normal tablets in controlling the blood pressure of hypertensive patient.
2) Madopar® HBS- containing L-dopa and benserazide- were drug was released and absorbed over a period of 6-8 hour and maintain substantial plasma concentration for parkinson’s patients.
3) Cytotech® -- containing misoprostol, a synthetic prostaglandin- E1 analog, for prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDS).
4) As it provides high concentration of drug within gastric mucosa, it is used to eradicate pylori (A causative organism for chronic gastritis and peptic ulcers).
5) 5-Fluorouracil has been successfully evaluated in patients with stomach neoplasm.
6) Developing HBS dosage form for tacrine provides a better delivery system and reduces its GI side effects in alzheimer’s patients.
7) Treatment of gastric and duodenal cancers.
Alza corporation has developed a gastroretentive platform for the OROS®
system, which showed prolong residence time in a dog model as the product remain in the canine stomach at 12 hrs. post dose and was frequently present at 21 hours.
Literature review
2. REVIEW OF LITERATURE
Inez Jimenez-Martinez, et al23 developed sustained release floating matrix tablets of captopril. In this work, the in vitro sustained release of captopril from Metolose SH 4000 SR/sodium bicarbonate floating tablets has been studied, varying the proportions of Metolose and bicarbonate. This was studied at two different compaction pressures. Other studied variables include the kinetics of the hydration volume, the matrices floating time and the matrix density. The results show that matrices compacted at 55MPa float in the dissolution medium for more than 8 h while those compacted at 165MPa float only when sodium bicarbonate is included in the formulation. The increase of the matrix polymer proportion increases the maximal hydration volume as well as the time to attain this maximum. The matrices hydration volume increases with the inclusion of sodium bicarbonate in the formulation. The matrix density is lower when compacted at 55MPa. The drug release constant (k) decreases and the exponent indicative of the release mechanism (n) increases with increasing polymer contents. The drug released with time is lesser when sodium bicarbonate is included in the formulation. Carbon dioxide bubbles obstruct the diffusion path and decrease the matrix coherence
Srivastava AK, et al.24 prepared floating matrix tablets of atenolol to prolong gastric residence time and increase drug bioavailability. The tablets were prepared by direct compression technique, using polymers such as HPMC K15M, K4M, Guargum (GG), and sodium carboxy methylcellulose (SCMC), alone or in combination, and other standard excipients. Tablets were evaluated for physical characteristics viz.
hardness, swelling index, floating capacity, thickness, and weight variation. The effect of effervescent on buoyancy and drug release pattern was also studied. In vitro release mechanism was evaluated by linear regression analysis. GG- and SCMC-based matrix tablets showed significantly greater swelling indices compared with other batches.
The tablets exhibited controlled and prolonged drug release profiles while floating over the dissolution medium.
Libo Zhao, et al25 studied Safety, tolerability and pharmacokinetics of phenoprolamine hydrochloride floating sustained-release tablets in healthy Chinese subjects. 116 volunteers were randomized into single- or multiple-dose groups for oral administration 30–240mg of PHFST once or 60–120mg twice daily. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters.
Pharmacokinetics was assessed by determining the plasma concentrations of phenoprolamine hydrochloride with a validated HPLC method. In single-dose studies, no severe adverse events were observed in volunteers, and all adverse events were mild; the percentages of treatment-emergent events judged to be possibly related to the drug were 3/6 in the 240mg dose group, 1/6 in the 180–210mg dose groups, and none in the 30–150mg dose groups; system exposure (AUC, Cmax) increased with respect to dose at 30–120 mg, whereas AUC raised disproportionately with dose escalating from 120 to 240 mg; the absorption of phenoprolamine hydrochloride was unaffected by food. In multiple studies, no safety concerns were revealed up to 7 days; steady-state plasma concentration was achieved after approximately 4–5 days of repeated twice-daily dosing. PHFST is safe and well tolerated in healthy Chinese subjects. The mean Cmax of PHFST is proportional to dose, but not the AUC.
C. Sauzet, et al 26 developed a gastro retentive floating dosage form of theophylline and evaluated. The aim of this study was to develop an innovative floating gastro retentive dosage form (GRDF). The developed technology induces a low-density dosage form containing high active pharmaceutical ingredient (API) concentration by using a hydrophobic dusty powder excipient under specific conditions. The newdosage formwas obtained by state of the art wet granulation manufacturing process. An experimental design using a discrete variable and four mixture variables was conducted in order to optimize API concentration and buoyancy of the new dosage form. An apparatus was developed to measure the apparent density of floating tablet. The GRDF was characterized for apparent density, buoyancy, porosity and dissolution using in vitro experimentations.
Streubel, et al.27 prepared single-unit floating tablets based on polypropylene foam powder and matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. A 17% wt/wt foam powder (based on mass of tablet) was achieved in vitro
Literature review
for at least 8 hours. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively.
M. Rosa JimCnez-Castellanos, et al.28 developed bioadhesive and floating drug delivery system for oral application of sotalol hydrochloride. The bioadhesion property and invitro dissolution study was carried out. In this study a new drug delivery system for a water-soluble beta-blocker drug, sotalol HCl, was developed utilizing both the concepts of adhesiveness and of flotation, in order to obtain a unique drug delivery system which could remain in the stomach for a much longer period of time. The floating and controlled-release properties of tablets consisting of cellulosic polymers were investigated. In order to validate the technological design of the new system, two different batches were made. In both cases, the time necessary for the tablets to begin to float was less than 30 min. Moreover, 90% of the drug content was released during the first 14 h. The bioadhesive property of the tablets was determined using rabbit tissue and a modified tensiometer. The new oral controlled- release system shows, at least in vitro, good characteristics in relation to three parameters: controlled release of the drug, bioadhesiveness in the stomach and intestine of rabbits and buoyancy in an acid medium.
Frances Stops, et al.29 developed and characterized calcium alginate beads as floating dosage forms. Floating calcium alginate beads, designed to improve drug bioavailability from oral preparations compared with that from many commercially available and modified release products, have been investigated as a possible gastro- retentive dosage form. A model drug, riboflavin, was also incorporated into the formula. The aims of the current work were (a) to obtain information regarding the structure, floating ability and changes that occurred when the dosage form was placed in aqueous media, (b) to investigate riboflavin release from the calcium alginate beads in physiologically relevant media prior to in vivo investigations. Physical properties of the calcium alginate beads were investigated. Using SEM and ESEM, externally the calcium alginate beads were spherical in shape, and internally, air filled cavities were present thereby enabling floatation of the beads. The calcium alginate beads remained buoyant for times in excess of 13 h, and the density of the calcium alginate beads was <1.000 g cm−3. Riboflavin release from the calcium alginate beads showed that riboflavin release was slow in acidic media, whilst in more alkali media,
riboflavin release was more rapid. The characterization studies showed that the calcium alginate beads could be considered as a potential gastro-retentive dosage form.
Yie W, Chien, et al.30 developed and optimized a floating delivery system for the oral controlled delivery of calcium. In this study the development of an optimized gastric floating drug delivery system is described. Statistical experimental design and data analysis using response surface methodology is also illustrated. A central, composite Box-Wilson design for the controlled release of calcium was used with 3 formulation variables: X1 (hydroxypropyl methylcellulose [HPMC] loading), X2 (citric acid loading), and X3 (magnesium stearate loading). Twenty formulations were prepared, and dissolution studies and floating kinetics were performed on these formulations. The dissolution data obtained were then fitted to the Power Law, and floating profiles were analyzed. Diffusion exponents obtained by Power Law were used as targeted response variables, and the constraints were placed on other response variables. All 3 formulation variables were found to be significant for the release properties (P < .05), while only HPMC loading was found to be significant for floating properties. Optimization of the formulations was achieved by applying the constrained optimization. The optimized formulation delivered calcium at the release rate of 40 mg/hr, with predicted n and T50% values at 0.93 and 3.29 hours, respectively. Experimentally, calcium was observed to release from the optimized formulation with n and T50% values of 0.89 (± 0.10) and 3.20 (± 0.21) hours, which showed an excellent agreement.
B.Y. Choi, et al.31 prepared alginate beads for floating drug delivery system and studied the effects of CO2 gas-forming agents. Floating beads were prepared from a sodium alginate solution containing CaCO3 or NaHCO3 as gas-forming agents. The solution was dropped to 1% CaCl2 solution containing 10% acetic acid for CO2 gas and gel formation. The effects of gas-forming agents on bead size and floating properties were investigated. As gas-forming agents increased, the size and floating properties increased. Bead porosity and volume average pore size, as well as the surface and cross-sectional morphology of the beads were examined with Mercury porosimetry and Scanning Electron Microscopy. NaHCO3 significantly increased porosity and pore diameter than CaCO3. Incorporation of CaCO3 into alginate
Literature review
solution resulted in smoother beads than those produced with NaHCO3. Gel strength analysis indicated that bead strength decreased with increasing gas-forming agent from 9 to 4 N. Beads incorporating CaCO3 exhibited significantly increased gel strength over control and NaHCO3-containing samples. Release characteristics of riboflavin as a model drug were studied in vitro. Release rate of riboflavin increased proportionally with addition of NaHCO3. However, increasing weight ratios of CaCO3 did not appreciably accelerate drug release. The results of these studies indicate that CaCO3 is superior to NaHCO3 as a gas forming agent in alginate bead preparations. The enhanced buoyancy and sustained release properties of CaCO3- containing beads make them an excellent candidate for floating drug dosage systems (FDDS).
Fell, et al.32 prepared floating alginate beads incorporating a Amoxycillin. The beads were produced by drop wise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hours and high drug-loading levels were achieved.
Baumgartner, et al.33 developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant.
AK Hilton and P.B. Deasy, 34 prepared oral sustained-release floating dosage form of amoxycillin trihydrate and invitro and in vivo evaluations were done. Various hydrophilic polymers were investigated for the preparation of amoxycillin trihydrate sustained-release (SRI tablets. The most suitable system contained a I : 2 ratio of hydroxypropylcellulose (HPCI to drug, which compressed easily and was not affected by alteration in normal compaction pressure. Intrinsic dissolution studies at pH 2 showed that reduction in drug loading decreased drug release, which being linear with time was characteristic of an eroding matrix with a hydrated layer. Examination of compacts over a wider range of pH showed the slowest rate of drug release at pH 6, corresponding to minimum solubility of the drug. Further formulatjon to enhance gastric retention time (GRT), by incorporation of a gas-venerating system, yielded either bi layer tablets which prematurely failed or large single-layer tablets which
remained buoyant for 6 h and had satisfactory in vitro SR. However. when the latter tablets were compared against conventional capsules in fasted humans at 500 mg equivalent dose of amoxycillin. their relative bioavailability was reduced to XO.S%
and other pharmacokinetic parameters indicated lack of improved efficacy.
Krogel I, et al.35 were developed and evaluated floating and pulsatile drug delivery systems based on a reservoir system consisting of a drug-containing effervescent core and a polymeric coating. Preliminary studies identified important core and coating properties for the two systems. The mechanical properties (puncture strength and elongation) of acrylic (Eudragit RS, RL or NE) and cellulosic (cellulose acetate, ethyl cellulose) polymers, which primarily determined the type of delivery system, were characterized with a puncture test in the dry and wet state. For the floating system, a polymer coating with a high elongation value and high water- and low CO2 permeabilities were selected (Eudragit RL/acetyltributyl citrate 20%, w/w) in order to initiate the effervescent reaction and the floating process rapidly, while for the pulsatile DDS, a weak, semi permeable film, which ruptured after a certain lag time was best (ethyl cellulose/dibutyl sebacate 20%, w/w). With the floating system, the polymeric coating did not retard the drug release. A polymer (cellulose acetate or hydroxyl propyl methylcellulose) was added to the core to control the drug release.
The time to flotation could be controlled by the composition (type of filler, concentration of effervescent agents) and hardness of the tablet core and the composition (type of polymer and plasticizer) and thickness of the coating. For the pulsatile system, a quick releasing core was formulated in order to obtain a rapid drug release after the rupture of the polymer coating. The lag time prior to the rapid drug release phase increased with increasing core hardness and coating level.
Yang, et al.36 developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (Tetracycline, Metronidazole, and Clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and poly (ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were
Literature review
incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release.
Incorporating a gas-generating layer consisting of sodium bicarbonate accomplished the floatation: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained float. The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole.
Ninan Ma, et al.37 Developed and evaluated new sustained-release floating microspheres of diltiazem hydrochloride. In this study a type of multi-unit floating alginate (Alg) microspheres was prepared by the ionotropic gelation method with calcium carbonate (CaCO3) being used as gas-forming agent. Attempts were made to enhance the drug encapsulation efficiency and delay the drug release by adding chitosan (Cs) into the gelation medium and by coating with Eudragit, respectively.
The gastrointestinal transit of optimized floating sustained release microspheres was compared with that of the non-floating system manufactured from identical material using the technique of gamma-scintigraphy in healthy human volunteers. It was found that the drug encapsulation efficiency of Cs–Alg microspheres was much higher than that of the Ca–Alg microspheres, and coating the microspheres with Eudragit RS could extend the drug release significantly. Both uncoated and coated microspheres were able to continuously float over the simulated gastric fluid (SGF) for 24 h in vitro. Prolonged gastric retention time (GRT) of over 5 h was achieved in the volunteer for the optimized coating floating microspheres (FM). In contrast, non- floating system (NFM) could be emptied within 2.5 h. In the present study, a multi- unit system with excellent floating ability, optimum drug entrapment efficiency and suitable drug release pattern has been developed.
Kouichi Nakamichi, et al.38 prepared and evaluated a floating dosage form of nicardipine hydrochloride and hydroxypropylmethylcellulose acetate succinate using a twin-screw extruder. A floating dosage form composed of nicardipine hydrochloride (NH) and hydroxyl propyl methylcellulose acetate succinate (enteric polymer) was prepared using a twin-screw extruder. By adjusting the position of the high-pressure screw elements in the immediate vicinity of die outlet, and by controlling the barrel
temperature, we were able to prepare a puffed dosage form with very small and uniform pores. It was found that the porosity and pore diameter could be controlled by the varying amount of calcium phosphate dihydrate. In the shaking test, the puffed dosage form was found to have excellent floating ability and mechanical strength in acid solution (JP First Fluid, pH 1.2). The dissolution profile of NH was controlled by the amount of wheat starch. In the dissolution test using JP Second Fluid (pH 6.8), rapid dissolution of NH and loss of buoyancy were observed. It was shown that the puffed dosage form, consisting of enteric polymer prepared using the twin-screw extruder, was very useful as a floating dosage form that was retained for a long period in the stomach.
Yong-Dan Tang, et al.39 developed sustained release of hydrophobic and hydrophilic drugs from a floating dosage form. Floating dosage forms enable the sustained delivery of drugs in the gastro-intestinal tract. In this study, a type of multi- unit floating gel bead was synthesized with calcium alginate, sunflower oil, and a drug of interest through an emulsification/gelation process. The alginate beads with oil addition were able to continuously float over the medium for 24 h under constant agitation while the non-oily beads could not. Three kinds of drugs with different hydrophilicities, aceclofenac, niacinamide and metoclopramide HCl, were tested in the study. The hydrophobic drug aceclofenac was released in a sustained manner for 24 h, due to the oil partitioning. With suitable modification, the beads were able to also release the hydrophilic drugs, niacinamide and metoclopramide HCl, for a similar duration. Therefore a floating dosage form that is able to sustain release both hydrophobic and hydrophilic drugs within its extended gastric retention time has been developed.
Sangekar,et al.40 studied the effect of food and specific gravity on the gastric retention time of floating (spec. grav. 0.96) and non-floating (spec. grav. 1.59) tablet formulations was investigated using gamma scintigraphy in humans. The results obtained indicate that the presence of food in the stomach appears to significantly prolong gastric retention of both the floating and non-floating tablets while specific gravity does not seem to play an important role in the residency time of the tablets in the stomach.
Literature review
Ingani, et al.41 published works have shown that hydro dynamically balanced systems (HBS) — i.e. sustained release oral dosage forms with a specific gravity lower than 1 and remaining buoyant on the gastric juice of the stomach — can have an enhanced gastrointestinal transit time. For this investigation, a double-layer sustained release compressed hydrophilic matrix was formulated in order to achieve a foreseeable and reproducible flotation of the tablet. A CO2 generating blend was, for this purpose, added to one of the layers, this gas being entrapped in the gelified hydrocolloid as liberated by the action of the gastric medium. The in vivo behavior of this floating tablet was then compared to a classical HBS capsule and to a similar but non-floating double-layer hydrophilic matrix on subjects alternatively in fasted or fed state. As these three dosage forms contain a riboflavin (RF) soluble derivative, it was possible to measure the RF urinary excretion rates and, consequently conclude that in vivo buoyancy is preponderant over bioadhesion for both floating capsules and tablets. These dosage forms also significantly increase the gastric residence time when compared to the non-floating dosage form. Compared to the classical HBS capsule, the floating tablet is showing in vivo equivalent floating properties when administered after a light meal and higher RF urinary excretion rates when administered to fasted subjects.
Sheth, et al.42 developed hydro dynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids
Xiaoqiang Xu, et al.42 developed three floating matrix formulations of Phenoporlamine hydrochloride based on gas forming agent. HPMC K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system.
Incorporation of sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed Non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of Phenoporlamine hydrochloride were conducted in six healthy male human
volunteers to compare the sustained release tablets with immediate release tablets.
Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).
Ziyaur rahman, et al.43 developed a bilayer-floating tablet (BFT) for Captopril using direct compression technology. HPMC, K-grade and effervescent mixture of citric acid and sodium bicarbonate formed the floating layer. The release layer contained captopril and various polymers such as HPMC-K15M, PVP-K30 and Carbopol 934p, alone or in combination with the drug. The floating behavior and in vitro dissolution studies were carried out in a USP 23 apparatus 2 in simulated gastric fluid (without enzyme, pH 1.2). Final formulation released approximately 95% drug in 24 h in vitro, while the floating lag time was 10 min and the tablet remained floatable throughout all studies. Final formulation followed the Higuchi release model and showed no significant change in physical appearance, drug content, floatability or in vitro dissolution pattern after storage at 45 °C/75% RH for three months.
P.S. Rajinikanth, et al. 44 developed and evaluated a novel floating in situ gelling system of amoxicillin for eradication of Helicobacter pylori. The aim of this study was to develop a new intra-gastric floating in situ gelling system for controlled delivery of amoxicillin for the treatment of peptic ulcer disease caused by Helicobacter pylori (H. pylori). Gellan based amoxicillin floating in situ gelling systems (AFIG) were prepared bydissolving varying concentrations of gellan gum in deionized water containing sodium citrate, to which varying concentrations of drug and calcium carbonate, as gas-forming agent, was added and dissolved by stirring.
The formulation variables like concentration of gellan gum and calcium carbonate significantly affected the in vitro drug release from the prepared AFIG. The in vivo H.
pylori clearance efficacy of prepared AFIG in reference to amoxicillin suspension following repeated oral administration to H. pylori infected Mongolian gerbils was examined by polymerase chain reaction (PCR) technique and by a microbial culture method. AFIG showed a significant anti-H. pylori effect in the in vivo gerbil model. It was noted that the required amount of amoxicillin for eradication of H. pylori was 10
Literature review
times less in AFIG than from the corresponding amoxicillin suspension. The results further substantiated that the prepared AFIG has feasibility of forming rigid gels in the gastric environment and eradicated H. pylori from the gastrointestinal tract more effectively than amoxicillin suspension because of the prolonged gastrointestinal residence time ofthe formulation.
Mahesh Chavanpatil, et al.45 prepared sustained release (SR)-gastro retentive dosage forms (GRDF) for Ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems.
Different polymers, such as psyllium husk, HPMC K100M, crosspovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 hrs. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions.
3. DRUG AND POLYMER PROFILE
3.1. DRUG PROFILE
Aceclofenac
Structure :
Chemical formula : C16H13Cl2NO4
Action and use :
Cyclo-oxygenase inhibitor; analgesic, anti-inflammatory.
Definition :
[[[2-[(2,6-
Dichlorophenyl)amino]phenyl]acetyl]oxy]acetic acid.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : White or almost white, crystalline powder.
Solubility :
Practically insoluble in water, freely soluble in acetone, soluble in ethanol (96 per cent) and HCl.
Melting point : 149° to 150°
Storage : Store in air tight container protected from light
Profiles
PHARMACOKINETICS & PHARMACODYNAMICS
Absorption : Well absorbed from the gastro intestinal tract.
Half ife : 3hrs Plasma protein binding: 99%
Volume of distribution: 25 litres
Elimination : Eliminated primarily through renal excretion with 70 – 80% of administerd dose found in urine as glucuronides.
IDENTIFICATION
A. Dissolve 50.0 mg in methanol R and dilute to 100.0 ml with the same solvent.
Dilute 2.0ml of the solution to 50.0 ml with methanol R. Examined between 220 nm and 370 nm (2.2.25), the solution shows an absorption maximum at 275 nm. The specific absorbance atthe absorption maximum is 320 to 350.
B. Infrared absorption spectrophotometry (2.2.24). Comparison_Ph. Eur.
reference spectrum of aceclofenac.
C. Dissolve about 10 mg in 10 ml of ethanol (96 per cent) R. To 1 ml of the solution, add 0.2 ml of a mixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassium ferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from light for 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protected from light for 15 min. A blue colour develops and a precipitate is formed.
3.2 POLYMER PROFILE
A) Hydroxy Propyl Methyl Cellulose32 Nonproprietary names:
BP : Hypromellose
Ph Eur : Methylhydroxypropylcellulosm USP : Hydroxy propyl methyl cellulose Regulatory status :
GRAS listed. Accepted as a food additive in Europe.
Included in the FDA. Inactive ingredients guide (ophthalmic preparation, oral capsules, suspensions, syrups, and tablets, topical and vaginal preparations).
Included in non parental medicines licensed in UK.
Synonyms :
HPMC; Methocel; Methyl cellulose propylene glycol ether; Methyl hydroxyl propyl cellulose; Metolose;
Pharmacoat; Cellulose; Hydroxy propyl methyl ether;
Culminal MHPC; E464.
Chemical name : Cellulose, 2-Hydroxypropyl methyl ether [9004-65-3]
Molecular formula : C12H23O6 (C12H22O5) nC12H23O5
Structure formula :
Profiles
Description :
Hydroxy propyl methylcellulose is a tasteless and odourless, white to slightly off white, fibrous or granular powder.
Typical Properties:
a) Sulphated ash: max 1.0 %
b) Auto ignition temperature: 360C c) Density : 0.5-0.7 gm/cm3 for Methocel
d) Melting point: Browns at 190-200C, chars at 225-230C. Glass transition temperature: 170-180oC.
e) Solubility: Soluble in cold water, forming a viscous colloidal solution;
practically insoluble in chloroform, ethanol (95%) and ether, but soluble in mixture of ethanol and dichloromethane.
f) Specific gravity: 1.12-1.15 g/cm3
g) Viscosity: A wide range of viscosity types are available.
h) Solubility and storage condition:
Solutions are stable between pH: 3-11. Increasing temperature reduces the viscosity of the solutions. HPMC undergoes a reversible sol to gel transformation upon heating and cooling respectively. The gel point is 50- 90C depending upon the grade of material.
HPMC powder is a stable material although it is hygroscopic after drying.
HPMC powder should be stored in a well-closed container, in a cool, dry place.
Safety :
HPMC is widely used as an excipient in oral and topical pharmaceutical formulations. It is also used extensively in cosmetics and food products.
LD50 (mouse, IP): 5 gm/kg.
LD50 (rat, IP): 5.2 gm/kg.
Functional category :
Tablet binder; Coating agent; Flavoring fixative; Tablet filler; Film former; Viscosity-increasing agent;
Suspending agent.
Applications 32 :
In oral products HPMC is primarily used as tablet binder, in film coating and as an extended release tablet matrix. Concentration between 2-5 %w/w may be used as a binder in either wet or dry granulation process.
High viscosity grade may be used to retard the release of water soluble drug from a matrix.
(B). Carbopol 53
Synonym :
Acritamer, Acrylic Acid Polymer, Carbopol, Carboxy Vinyl Polymer.
Non proprietary names: B.P: carbomer U.S.P: carbomer
Chemical name : Carboxypolymethylene.
Profiles
Structure :
Molecular weight :
Carbomer resins are theoretically estimated at 7 × 105 to 4 × 109.
Category :
Emulsifying agent, suspending agent, tablet binder, viscosity- enhancing agent
Description :
Carbomers are white colored, fluffy, acidic, hygroscopic powder with slightly characteristic odour.
Solubility :
Soluble in water, and after neutralization, in ethanol (95
%) and glycerin.
Viscosity :
29,400-39,400 cps (0.5%w/v), carbomers disperse in water to form acidic colloidal solutions of low. viscosity which when neutralized produces highly viscous gels.
Stability and storage :
Carbomers are stable, though hygroscopic materials
