Formulation and evaluation of buccal delivery systems for an antiinflammatory drug
M. Pharm. dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Mr. SUBHRO JYOTI GUPTA
Under the Guidance of
Dr. C Mallikarjuna Setty
PROFESSOR
Department Of Pharmaceutics,
The Oxford College of Pharmacy,
No.6/9, 1st Cross, Begur Road,
Hongasandra, Bengaluru –560 068
Karnataka
ANNNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name and address of candidate / Subhro Jyoti Guptac/o Bipul Jyoti Gupta
SHANTONEER Opp to F.C.I Office
Post. Suri , Dist.Birbhum
731101
West Bengal
2 / Name of institution / THE OXFORD COLLEGE OF PHARMACY,
No.6/9, 1st Cross, Begur Road,
Hongasandra, Bengaluru –560 068
Karnataka
3 / Course of study and subject / M. Pharm
(Pharmaceutics)
4 / Date of admission /
30.07.2013
5 / Title of the project / Formulation and Evaluation of Buccal delivery systems for an anti-inflammatory drug.6 / BRIEF RESUME OF INTENDED WORK
6.1 NEED FOR THE STUDY:
Antiinflammation drugs have been used in the form of tablets, capsule, topical gells, etc. Of the dosage forms used, orally administered popular tablets, capsules, etc., have the following problems,
- They undergo 1st pass metabolism,
- Difficult to be administered and swallowed by old people,
- Poor and variable bioavailability,
- Poor patient compliance, etc.
- Ease of Administration to the patient who cannot swallow, such as the elderly, stroke victims, bedridden patients, patient affected by renal failure and patient who refuse to swallow such as pediatric, geriatric & psychiatric patients.
- No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling and do not have immediate access to water.
- Rapid dissolution and absorption of the drug, which will produce quick onset of action.
- Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases bioavailability of drug is increased.
- Pregastric absorption can result in improved bioavailability and as a result of reduced dosage; improve clinical performance through a reduction of unwanted effects.
- Good mouth feel property helps to change the perception of medication as bitter formulation particularly in pediatric patient.
- The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety.
- New business opportunity like product differentiation, product promotion, patent extensions and life cycle management.
- An increased bioavailability, particularly in cases of insoluble and hydrophobic drugs.
6.2 REVIEW OF LITERATURE
- The development of buccal formulations (tablets) based on chitosan microspheres containing chlorhexidine diacetate. The microparticles were prepared by a spray-drying technique, their morphological characteristics were studied by scanning electron microscopy and the in vitro release behaviour was investigated in pH 7.0 USP buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in vitro than does chlorhexidine powder. The anti-microbial activity of the microparticles was investigated as minimum inhibitory concentration, minimum bacterial concentration and killing time. The loading of chlorhexidine into chitosan is able to maintain or improve the anti-microbial activity of the drug. The improvement is particularly high against Candida albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty microparticles have an anti-microbial activity due to the polymer itself. Buccal tablets were prepared by direct compression of the microparticles with mannitol alone or with sodium alginate. After their in vivo administration the determination of chlorhexidine in saliva showed the capacity of these formulations to give a prolonged release of the drug in the buccal cavity(1).
- Termination of therapy is possible . Permits localization of drug to the oral cavity for extended period of time. . Ease of administration .Avoids first pass metabolism. .Reduction in dose can be achieved .Selective use of therapeutic agents like peptides, proteins and ionized species can be achieved.(2)
- Drugs which are unstable in acidic environment of stomach or destroyed by the alkaline environment of intestine can be given by this route . Administration of drugs with poor bioavailablity. It follows passive diffusion. Dissolution of drug is easy unlike in case of rectal and transdermal route(2)
- Oral mucosamucous membranes / mucosae / singular mucosa :-That are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion . They line various body cavities that are exposed to the external environment and internal organs . It is at several places continuous with skin - at the nostrils , the lips , the ears , the genital area , and the anus .The sticky thick fluid secreted by the mucous membranesis termed mucus(3)
- The average thickness of various regions of the human oral mucosaEpithelium :- Basement membrane :- Boundary between basal layer (epithelium) & connective tissue (lamina propria & submucosa)Submucosa layer :-Mucus : Secreted by goblet cells / special endocrine glandsConnective tissue : Collagen, elastic fibers, cellular components(3)
- ADVANTAGES Ease of administration and terminationhostile environment than GIT Directly.Fast cellular recovery & easily modify microenvironment Lower intersubject variability as compared to transdermal patches. Less Abundance of blood vessel Avoids first pass effect(4)
- Mast cells are mobile granule-containing secretory cells that are distributed preferentially about the microvascular endothelium in oral mucosa and dental pulp.Mast cell proteases may contribute to alterations in basement membranes in inflammation in the oral cavity, such as the disruptions that allow cytotoxic lymphocytes to enter the epithelium in oral lichen planus(4)
- Research suggests that there is an interrelationship between oral infection, inflammation and systemic health. Patients, dental healthcare professionals and other health care providers should be aware of the consistent relationships between oral inflammation and systemic diseases. They should value the need to modify assessment, prevention, and treatment protocols to improve the oral health(5)
- PAF, or platelet-activating factor, is a family of structurally related phospholipids (1-O-alkyl/acyl/alkenyl-2-acetylsn-glycero-3-phosphocholine) which possesses a wide spectrum of potent pro-inflammatory actions. These phospholipids are synthesized by a diverse array of cells, including neutrophilic polymorphonuclear leukocytes (PMN), platelets, mast cells, monocytes/macrophages, vascular endothelial cells, and lymphocytes. PAF targets these and other cells via specific, G-protein-coupled receptors to initiate intracrine, autocrine, paracrine, and juxtacrine cell activation. Of importance, these unique acetylated phospholipids are frequently synthesized in concert with pro-inflammatory lipid mediators derived from arachidonic acid. Since PAF synergizes with these and other mediators to amplify the inflammatory response, it seems likely that PAF plays an integral, perhaps pivotal, role in acute and chronic inflammatory processes. PAF is present in the mixed saliva of dentate, but not edentulous, human subjects. The levels of PAF in mixed saliva or in gingival crevicular fluid and tissues are significantly increased during oral inflammatory conditions such as periodontitis and mucositis. Interestingly, the levels of salivary PAF correlate with the extent/severity of these oral diseases. These observations suggest that PAF may participate in pathophysiologic events during the course of oral inflammation. The availability of specific PAF receptor antagonists and human recombinant PAF-acetylhydrolase (PAF-AH), a plasma enzyme which rapidly destroys PAF, should provide clinical tools for the investigation of the role of PAF in these and other inflammatory disorders; and perhaps, ultimately, some of these reagents may prove to be therapeutically useful in the treatment and management of these conditions(4)
- Ease of Administration to the patient who cannot swallow, such as the elderly, stroke victims, bedridden patients, patient affected by renal failure and patient who refuse to swallow such as pediatric, geriatric & psychiatric patients.No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling and do not have immediate access to water.The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety(6)
- Administration Instructions
- A new bioadhesive polymer patch formulation for buprenorphine controlled delivery and consisting of polyisobutylene, polyisoprene, and Carbopol® 934P was prepared using a two-roll milling method. Carbopol® 934P was the bioadhesive of choice for the current formulation because it demonstrated a higher average peeling strength than hydroxypropyl methylcellulose, chitosan, or acacia as measured during in vitro testing. Other in vitro analyses showed that the milling process did not alter the viscosity or the thermodynamic and rheologic properties of polyisobutylene and polyisoprene. Nearly 75% of the buprenorphine was released from the patches following a 24 hour incubation in phosphate buffer (pH = 7). Data obtained from dissolution studies suggested that the major mechanism of buprenorphine release is patch swelling. It was also shown that patch adhesion increased with increasing thickness and up to three months of aging had little effect on adhesive properties. In addition, this formulation maintained the majority of its adhesive strength for at least 24 hours with a linear decline in average peeling load thereafter. In conclusion, buccal patches consisting of a homogeneous mixture of polyisobutylene, polyisoprene, and Carbopol® 934P formed by a two-roll milling process appear to possess physical properties that are well suited for the transmucosal controlled delivery of buprenorphine(8)
- Buccal films of salbutamol sulphate were prepared using three different polymers in various proportions and combinations. The physicochemical parameters like thickness, density, folding endurance, swelling index, mucoadhesive strength based on shear stress and tensile strength, water permeability, drug content and drug release characteristics were evaluated in order to study the effect of polymer and its concentration on the drug release. The properties of the drug free buccal films were compared with the films obtained after drug incorporation in order to study the effect of drug loading on the film characteristics. The thickness and density of all the films produced were in the range of 0.15 to 0.24 mm and 1.104 to 1.445 g/cm3, respectively. High folding endurance was observed for films containing ethyl cellulose and its combination with hydroxypropylmethyl cellulose. The swelling index was found to be high for formulation F2 containing Eudragit RL100, 6% w/ v and 3.2 g of glycerol 40% w/w. The results of the mucoadhesive strength measurement based on shear stress indicated that the buccal films of formulation F4 containing each 3% of hydroxypropylmethyl cellulose and ethyl cellulose exhibited a high value, but the tensile strength measurement studies indicated high mucoadhesive strength for formulation F2. Water permeability was found to be high for formulation F1 containing 6% w/v of Eudragit RL 100 and 2.4 g of glycerol 40% w/w. Drug content uniformity was observed for all films. The drug release studies indicated the first order controlled release kinetics in all cases and the release was extended up to 8 h for formulation F4. It was also observed that the lower the permeability coefficient the greater was the extended release characteristics for the buccal films. Finally it was concluded that the polymers and their combination influenced the film properties as well as release characteristics(9)
- The purpose of this study was to develop and optimize formulations of mucoadhesive patches of Ropinirole. The Ropinirole is a non-ergoline dopamine agonist with high relative specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes. Ropinirole buccal patches are prepared using different mucoadhesive polymers by solvent casting technique. Buccal patches were characterized for parameters like physical appearance and surface texture, mass uniformity, thickness, folding endurance, swelling index, surface pH, drug content uniformity, in-vitro residence time, Bursting strength, Ex-vivo mucoadhesive force, Ex-vivo permeation study, in-vitro drug release study and drugexcipients interaction study. The release of Ropinirole from all the formulations was in the range of 76.64 to 90.73% at the end of 8 hrs. The permeation of the drug through the buccal mucosa was found to be release dependant in the range of 73.91 to 85.52%. Drug compatibility with excipients was checked by FTIR studies and it revealed that, there was no incompatibility of the drug with the excipients used. Release of Ropinirole from all patches followed zero order and mechanism was diffusion rate limited. The best mucoadhesive performance and matrix controlled release was exhibited by the formulation RBP8. From this study, it can be concluded that, these formulations of Ropinirole mucoadhesive buccal patches promising one as the controlled drug delivery, shows moderate swelling, convenient resident time will lead to improve the bioavailability and greater therapeutic efficacy. (10)
- The goal of present investigation highlights the formulation and evaluation of mucoadhesive buccal patches of Tramadol hydrochloride. The mucoadhesive buccal patches of Tramadol hydrochloride were prepared by solvent casting technique using various concentrations of Chitosan polymer. The formulated patches were evaluated for their physicochemical parameters like thickness, weight variation, surface pH, content uniformity, folding endurance swelling percentage studies and in vitro residence time. In vitro release studies were performed with pH 6.8 phosphate buffer solution. Good results were obtained both in physicochemical and in vitro studies. The films were exhibited controlled release more than six hours. The in-vitro release datas were fit to different equation and kinetic models to explain release profiles. The best mucoadhesive performance and matrix controlled release was exhibited by the formulation R6. The formulation was found be right and suitable candidate for the formulation of Tramadol HCL mucoadhesive buccal patches for therapeutic use.(11)
oBuccal delivery is considered to be an important alternative to the per oral route for the systemic administration of drugs. The aim of the study was to develop and evaluate mucoadhesive buccal films of Carvedilol for systemic delivery. This paper explains the fabrication of new bilayered films consisting of a drug containing mucoadhesive layer and a drug free backing layer. The films were fabricated by a casting technique with different polymer combinations and were evaluated for in vitro release, thickness, microenvironment pH, drug content uniformity, ex vivo residence time, uniformity of weight, moisture absorption studies. The physicochemical interactions between Carvedilol and polymers were investigated by FTIR Spectroscopy. The present buccal formulation can be an ideal system to improve the bioavailability of the drug by avoiding hepatic first-pass metabolism.(i2)
6.3.OBJECTIVE OF THE STUDY:
The main objective is to :
To formulate and evaluate novel buccal delivery systems for anti-inflammatory drug,
To characterize the formulations for drug interaction, stability, etc.
7.0 Materials and methods :
Materials:
Drug : Analgesic/Anti-inflammatory.
Excipients : It will be selected after the compatibility studies.
Polymers : HPMC, sodium CMC, Ethylcellulose, methyl cellulose, natural gums, etc.
Method of preparation: Buccal delivery systems will be prepared by either established (solvent-casting, compression, etc) or a new method will be explored.
7.1 Source of the data :
The data was obtained from Pubmed, Science direct and Medline, internet Facilities, various books, literature search and related articles from the library of The Oxford College Of Pharmacy.
7.2 Method of collection data:
The data will be collected from the prepared formulation on the basis of :
Preformulation studies
Compatibility studies
Bulk density
Tapped density
Angle of repose
Carr’s Index
Hausner’s ratio
Evaluation of the formulation
Friability test
Hardness test
Disintegration test
Dissolution studies.
Stability studies.
Swelling test
8.LIST OF REFERENCES :-
1.Rout of drug administration by Fago sliu Abubakar.
2.Advantages of Buccal dryg delivery system
3Laurence J Walsh,Mast cell and oral inflammation
4.Gurenilian JR,Inflammation :The relation between oral health and systemic disease.
5.PAF a Putative medication of oral inflammation.
6. Bradoo R. Fast Dissolving Drug Delivery Systems. JAMA India 2001; 4 (10): 27-31.Z
8. Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Formulation, In-vitro Adhesion and Release Properties9. Pavankumar CV,RamakrishnaV, Formulation and evaluation of buccal films of salbutamol sulphate
10.Formulation and Evaluation of Ropinirole Buccal Patches Using Different Mucoadhesive drugs
Formulation and evaluation of mucoadhesive buccal patches of Tramadol hydrochloride
11. Yogananda *1, Rakesh Bulugondla1, T.S. Nagaraja1, Snehalatha1, LakshmiRadhika .G1.12Formulation and evaluation of mucoadhesive buccal patches of Tramadol hydrochloride
9 / DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BECONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS?
“NOT REQUIRED”
Has ethical clearance been obtained from your institution in case
“NOT REQUIRED
9 / Signature of the candidate:
10 /
Remarks of the Guide: / This project has been discussed and the work will be carried out under my guidance and supervision as an official guide. This research work will be of great importance to the pharmaceutical field.
11 / Name and Designation of:
11.1 Institutional Guide: / Dr. C Mallikarjuna Setty
PROFESSOR
11.2 Signature:
11.3 Co-Guide: / NA
11.4 Signature: / NA
11.5 Head of the Department: / Dr. C Mallikarjuna Setty.
Professor &Head, Dept. of Pharmaceutics
11.6Signature
12 / 12.1 Remarks of the Principal / Recommended and forwarded for scrutiny
12.2 Signature / Dr. PADMAA M. PAARAKH
1