Indo American Journal of Pharmaceutical Research, 2013
Journal home page: http://www.iajpr.com/index.php/en/
ISSN NO: 2231-6876
INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH
DESIGN AND EVALUATION OF NOVEL BI-LAYERED TABLET FOR THE EFFECTIVE TREATMENT OF HYPERTENSION Rohan Ghadi, Harshal Garse, Dr.Neha Dand, Dr.Vilasrao Kadam, Nilkamal Waghmare. Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, India. ARTICLE INFO Article history Received 10/12/2013 Available online 30/12/2013
Keywords Orodispersible, Mucoadhesive, Bioavailability, Antihypertensives.
ABSTRACT The drugs today are being synthesised by a variety of modern chemical techniques. The new chemical entities thus designed have a variety of issues which hamper their translation to actual market. These issues are low aqueous solubility, first pass metabolism, low efficacy, potential side effects, pH stability problems, patient non-compliance to name a few. The leaps taken by current medical research prove the benefits of using two drugs simultaneously for effective treatment and management of disorders like hypertension, hyperlipedemia, infections etc. But combining two drugs which would have completely unrelated challenges would prove to be herculean task for any formulator. The present work focuses on this very challenge of combining two commonly prescribed antihypertensive agents’ metoprolol tartrate and hydrochlorothiazide, first of which suffers from extensive first pass metabolism and the latter from poor patient compliance. Thus a bilayered tablet is formulated, wherein the first later is an orodispersible layer of hydrochlorothiazide formulated using Primogel as the superdisintegrant and Galen IQ 720 as the diluent and the second one is the mucoadhesive layer of metoprolol tartrate prepared by using sodium carboxymethylcellulose as the mucoadhesive polymer. Both the layers were evaluated for physical characteristics, in vitro drug release and assay. Additionally, the orodispersible layer was assessed for in vitro wetting time, in vitro disintegration time while the mucoadhesive layer was evaluated for mucoadhesive strength, ex vivo permeation and surface pH.
Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as Rohan Ghadi, et al. Design and evaluation of novel bi-layered tablet for the effective treatment of hypertension. Indo American Journal Of Pharm Research.2013:3(12).
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Corresponding author Rohan Ghadi Affiliation: Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, India Email ID:
[email protected] Contact: +91 9821538154
ISSN NO: 2231-6876
INTRODUCTION: In the present scenario the prime focus has shifted towards combination therapy for the treatment of various diseases and disorders such as hypertension and diabetes requiring long term therapy. Combination therapy has an edge over monotherapy because it minimizes the dose dependent side effects and increases the overall clinical performance of the drugs [1]. Hypertension is one of the major risks associated with heart disease. It is not a disease in itself, but it is an important risk factor for cardiovascular mortality and morbidity. Hypertension is the principal cause of stroke; a major risk factor for coronary artery disease and its attendant complications, myocardial infarction and sudden cardiac death [2].The prevalence of hypertension increases with advancing age; for example, about 50% of people between the ages of 60 and 69 years old have hypertension, and the prevalence is further increased beyond age 70 [3]. However, it is a known fact that a number of potential cardiovascular drug molecules have bioavailability problems related to acid instability, enzymatic degradation and poor water solubility which may lead to inadequate and erratic oral absorption [4-6]. They also have a short half life due to extensive first pass metabolism and therefore short duration of action. Hence they require frequent administration which causes discomfort to geriatric population [6-11]. When a combination of such drugs is formulated, it may lead to non optimal bioavailability. Vanderbist et al. [12] had patented a technique for delivering two drugs having different absorption window. The drug having absorption window in the stomach was compressed as a conventional tablet which was then layered upon the enteric coated second tablet of drug having its absorption window in intestine. But till date no such reports have been published where drugs having different challenges have been formulated effectively. Thus the aim of the present work was to deliver the drugs having completely unrelated challenges of one drug undergoing extensive first pass metabolism and the second drug having poor patient acceptability or demonstrating compliance issues. The objective of the proposed invention comprised of formulating a bi-layered tablet. One of the layers was a buccal mucoadhesive layer which would enable the absorption of the drug having a drawback of extensive first pass metabolism directly into the systemic circulation by direct absorption in the capillary network present just below the buccal mucosa. The second layer was an orally disintegrating layer of the second drug which would disintegrate within 30 seconds to form a uniform, palatable dispersion to be swallowed and would help in rapid absorption of the drug from the stomach making the drug more patient compliant. So the primary aim was to enhance compliance by using a single bi-layered tablet that can be taken once or twice daily without chewing or without the aid of water. In the present study a combination drug therapy of Metoprolol tartrate and Hydrochlorothiazide was selected for the treatment of hypertension; to allow these agents of different mechanism of action to complement each other which would reduce the patient’s blood pressure and also encourage the use of lower doses of these drugs individually [13]. Using low doses of these two different agents could minimize the clinical and metabolic side effects that occur with the maximal dosages of the individual components of the combined tablet. The other rationale for selection of this combination is that the antihypertensive efficacy of metoprolol is enhanced by combining with a thiazide diuretic like hydrochlorothiazide [14, 15]. Also metoprolol and hydrochlorothiazide combinations have been found to be effective and well tolerated in elderly patients [16, 17]. Kannan et al have designed and evaluated an oral bilayer tablet containing Metoprolol succinate as sustained release and hydrochlorothiazide as immediate release layer. Sustained layer were prepared by wet granulation method using different grades of HPMC (HPMC K4M and HPMC K100M) as hydrophilic polymers and immediate release layer prepared by direct compression. The study concluded that bilayer tablets of Metoprolol succinate and Hydrochlorothiazide as an alternative to the conventional dosage form [18]. Metoprolol tartrate (MT) is a competitive β1-selective adrenoreceptor-blocking drug that is devoid of intrinsic sympathomimetic activity. It is one of the most commonly used β blockers in case of treatment and management of hypertension and angina. Although it is well absorbed in the gastrointestinal tract, the bioavailability of MT is extremely low which can be attributed to its extensive first pass metabolism of 40-60 %. It means that, this amount of drug is not absorbed [19].If more amount of drug reaches the systemic circulation after bypassing the liver, it would lead to better pharmacokinetics and hence better pharmacodynamics. This improvement was brought about by incorporating MT into the buccal mucoadhesive layer to facilitate its direct absorption into the systemic circulation which could reduce its dose. The physicochemical properties of MT, its suitable half-life (4 hours), and its low molecular weight 684.8 make it a suitable candidate for administration by the buccal route [20]. Hydrochlorothiazide (HCTZ) is a thiazide diuretic commonly prescribed in geriatric patients for the treatment of hypertension, congestive heart failure and edema [21].The geriatric population finds it inconvenient to ingest conventional solid dosage forms such as tablets and capsules due to an impaired ability to swallow. This leads to patient noncompliance and potentially prolonged duration of treatment or ineffective therapy. This issue was resolved through the incorporation of HCTZ in the orally disintegrating layer that can dissolve or disperse in the saliva and then the saliva containing the drug is swallowed without water. Also the drug has an absorption window limited to the upper small intestine. It is mostly absorbed from the duodenum and the first part of the jejunum [22]. If it is formulated as orally disintegrating layer it will disperse or dissolve immediately in the saliva. The saliva containing the dissolved or dispersed medicament is then swallowed and hence it will be in solution form before it reaches the site of absorption. Therefore it will increase the bioavailability and overall clinical performance. HCTZ has a bland taste and does not require taste masking and hence provides an added advantage. Hence it was decided to incorporate HCTZ as the orally disintegrating layer. Thus the objective of present work is efficient management of hypertension, better patient compliance, improved efficacy and lesser side effects from these drugs. It would give the physicians a better medication and alternative to manage and treat hypertension. It would help the pharmaceutical companies dealing with these drugs by giving them a new avenue for research and making their product more efficacious and commercially viable.
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MATERIAL AND METHODS: Materials All the materials used were of pharmaceutical grade purity. Metoprolol tartrate was obtained as a gift sample from Indoco Remedies Limited, Mumbai. Hydrochlorothiazide was kindly gifted by Sun Pharmaceuticals, Vadodara. Pharmatose DCL 11, Galen IQ 720, Lactose, Ac-Di-Sol, Primojel, Crosspovidone, Indion 414, SCMC, Sodium Alginate, Guar Gum, HPMC K15M, Carbopol 974P and Polycarbophil AA1 were of pharmaceutical grade. All other solvents and reagents were of analytical grades. We extend our heartfelt gratitude to University of Mumbai for funding the work under Minor Research Grant Scheme (Project no. 366 of 2012). Methods A) Formulation Development: Formulation of buccal mucoadhesive tablets of Metoprolol tartrate: Buccal mucoadhesive drug delivery system utilizes the property of bioadhesion of certain polymers which become adhesive on hydration and hence can be used for targeting a drug to a particular region of the body for extended periods of time. In recent era many researchers are focusing on targeting a drug or formulation in a particular region of the body for specific period of time. This is not just for targeting of drugs to a particular or effected part of the body but also to better control of systemic drug delivery to minimize side effects. Drugs that are absorbed through buccal mucosal region enter directly into the blood stream and thus they are not inactivated by enzymatic degradation and pre systemic metabolism. Buccal mucoadhesive tablets prolong the residence time which ensures satisfactory drug release in a unidirectional fashion to the mucosa and avoids loss of drug resulting from wash out with saliva [23, 24]. Proposed design:
Fig 1.0 Mucoadhesive tablet layer of Metoprolol tartrate Procedure: MT, lactose, PVP K-30 and various mucoadhesive polymers were first sieved through #100 mesh and were mixed in geometric proportion and blended for 5 mins. The dry mixture was granulated by using the distilled water. The wet mass was passed through 10 mesh and dried at 100 °C for 15 mins. The dried granules were passed through #16 mesh superimposed on #44 mesh. Granules, 10 % fines, talc and magnesium stearate was blended for 2 mins. The granules ready for compression were compressed on single punch compression machine on 8 mm flat beveled punches.
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Selection of mucoadhesive polymers: Mucoadhesive polymers are defined as polymers that can adhere onto a biological substrate. Polymers, which can adhere to either hard or soft tissue, have been used for many years in surgery and dentistry. An ideal polymer for mucoadhesive drug delivery system should have the following characteristics [25]. It should be non-toxic, nonirritant and free from leachable impurities. It should have good spreadability, wetting property and ability to swell. It should be soluble, bioerodible or biodegradable and the polymer pH should be biocompatible. It should adhere quickly to buccal mucosa and should possess sufficient mechanical strength. It should be easily available and cost should not be high.
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Classification of polymers [26]: Table 1: Mucoadhesive polymers in buccal delivery Criteria Source
Categories Seminatural/natural Semi-Synthetic
Synthetic
Examples Agarose, chitosan, gelatin, hyaluronic acid and Various gums (guar, hakea, xanthan, gellan, carragenan, pectin, and sodium alginate) Cellulose derivatives [CMC, thiolated CMC, SCMC, HEC, HPC, HPMC, MC] Poly(acrylic acid)-based polymers [CP, PC, PAA, polyacrylates, poly(methylvinylether-co-methacrylic acid), Carbopol 974 P, Polycarbophil AA1
For the proposed formulation various natural and synthetic polymers were tried to achieve the desired degree of mucoadhesion strength. To assess the suitability of mucoadhesive polymers various formulations were prepared as shown in table 1.1 below. Table 1.1: Trials for selection of mucoadhesive polymers Ingredients Metoprolol tartrate Lactose Carbopol 974 P HPMC K15M Polycarbophil AA1 Sodium Alginate Guar Gum SCMC PVP K-30 Magnesium stearate Talc Total
Formulation Code (mg/tab) M-1 M-2 M-3 50 50 50 87 82 87 5 10 5 5 5 5 1 1 1 2 2 2 150 150 150
M-4 50 42 50 5 1 2 150
M-5 50 42 50 5 1 2 150
M-6 50 82 10 5 1 2 150
Selection of penetration enhancer: Membrane permeation is the limiting factor for many drugs in the development of buccal drug delivery system. The epithelium that lines the buccal mucosa is a very effective barrier to the absorption of drugs. Substances that facilitate permeation of drugs through buccal mucosa are referred as permeation enhancers. The selection of enhancer and its efficacy depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other excipients. These permeation enhancers should be safe and non-toxic, pharmacologically and chemically inert, non-irritant, and non-allergenic. Classification of Penetration Enhancers [27]:
Examples
Chelators Surfactants
EDTA, citric acid, sodium salicylate, methoxy salicylates. Sodium lauryl sulphate, polyoxyethylene, Polyoxyethylene-9-laurylether, Polyoxythylene-20-cetylether, Benzalkonium chloride, 23-lauryl ether, cetylpyridinium chloride, cetyltrimethyl ammonium bromide. Sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate. Oleic acid, capric acid, lauric acid, lauric acid/ propylene glycol, methyloleate, lysophosphatidylcholine, phosphatidylcholine. unsaturated cyclic ureas. cyclodextrins. aprotinin, azone, cyclodextrin, dextran sulfate, menthol, polysorbate 80, sulfoxides and various alkyl glycosides. chitosan-cysteine, Poly (acrylic acid)-homocysteine, polycarbophil-cysteine, polycarbophil-cysteine/GSH,
Bile salts Fatty acids Non-surfactants Inclusion complexes Others Thiolated polymers
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Categories
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Table1.2: Penetration enhancers in buccal delivery
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To assess the suitability of penetration enhancers various formulations were prepared as shown in table 1.3 below. Table 1.3: Trials for selection of penetration enhancers Ingredients Metoprolol tartrate Lactose SCMC SLS Bile salt PVP K-30 Magnesium stearate Talc Total
Formulation Code (mg/tab) M-7 M-8 M-9 50 50 50 81 80 79 10 10 10 1 2 3 5 5 5 1 1 1 2 2 2 150 150 150
M-10 50 81 10 1 5 1 2 150
M-11 50 80 10 2 5 1 2 150
M-12 50 79 10 3 5 1 2 150
2) Selection and application of backing membrane of Ethyl Cellulose Application of an impermeable backing layer on buccal mucoadhesive layer was considered to prevent drug loss and for the patient’s convenience. Also the drug MT has a very bitter taste and in the proposed formulation the taste was not masked. Therefore a backing membrane was essential to prevent the drug from being swallowed and pose a problem of inconvenience and being unpalatable to the patient. Ethyl cellulose [28] was used as backing layer material because of its hydrophobicity, low water permeability and moderate flexibility. Therefore it was found to be a good candidate for backing application. Procedure: The granules for backing membrane of ethyl cellulose were prepared by wet granulation technique. The dry mixture of the backing polymer, ethyl cellulose and the colour erythrosine was granulated by using acetone. The wet mass was passed through 10 mesh. The granules were first air dried for 10 mins. Then they were further dried at 40 °C for 15 mins. The dried granules were passed through #16 mesh superimposed on #44 mesh. The granules obtained were used to give a backing membrane to the buccal mucoadhesive tablets by compression method. To assess the quantity of GRC of ethyl cellulose required to give an efficient backing membrane various trials were conducted as shown in table 1.4 below. Table 1.3:Trials for selection of penetration enhancers Ingredients Tablet weight Ethyl cellulose (GRC)
Formulation Code (mg/tab) M-13 M-14 M-15 150 150 150 10 20 30
M-16 150 40
M-17 150 50
For the application of the backing membrane, the buccal mucoadhesive tablets compressed on 8 mm flat beveled punch were then transferred to 9 mm die and a layer of EC was then compressed on it.
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3) Formulation of orally disintegrating layer of Hydrochlorothiazide Although tablets and capsules are most preferred drug delivery systems, some patient group such as pediatrics, geriatrics and bedridden or disabled patients experience difficulty in swallowing such dosage forms. Many pharmaceutical manufacturers are now concentrating on ODT technology and trying to offer a wider choice of pharmaceutical actives covering many therapeutic categories to both physicians and patients. To meet these medical needs, formulators are trying to devote considerable efforts to develop a novel dosage form known as orally disintegrating tablet (ODT), which can disintegrate rapidly in the saliva without water [29]. Orally disintegrating tablet is the fast growing and highly accepted drug delivery system because of convenience of self administration, compactness and easy manufacturing. Proposed design:
Fig 1.1 Orodispersible tablet layer of Hydrochlorothiazide
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Procedure: Hydrochlorothiazide, Galen IQ 720and various superdisintegrants were first sieved through mesh #100. Hydrochlorothiazide and other ingredients like diluents, superdisintegrants, sweetener and glidant were mixed together and finally lubricant and flavor was added. Powder was compressed on single punch machine using flat beveled 9 mm punch. Selection of diluents: Diluents are inactive substances used as carrier for the active ingredients. They are fillers used to make required bulk of the tablet when the drug dosage itself is inadequate to produce the bulk. Secondary reason is to provide better tablet properties such as improve cohesion, to permit use of direct compression manufacturing or to promote flow [30]. An ideal diluent should have following properties: 1. It must be non toxic and commercially available in acceptable grade 2. The cost must be low and it must be physiologically inert. 3. It must be physically & chemically stable by itself& in combination with the drugs. 4. It must be free from all microbial contamination. 5. It should not alter the bioavailability of drug. 6. It must be colour compatible. In direct compression technology various specialized diluents can be employed which help in direct compression of tablet blend. The commonly used directly compressible diluents are, Spray dried lactose Directly compressed starch-Sta Rx 1500 Hydrolyzed starch-Emdex and Celutab Microcrystalline cellulose-Avicel (PH 101and PH 102) Mannitol, Sorbitol Sucrose- Sugartab, DiPac, Nutab To assess the suitability of diluents various formulations were prepared as shown in table1.5 below and the flow properties of the blend were evaluated. Table 1.3: Trials for selection of penetration enhancers Ingredients Hydrochlorothiazide Galen IQ 720 Pharmatose DCL 11 Primojel Magnesium stearate Aerosil Sodium saccharin Mint powder Brilliant green Total weight
Formulation code (mg/tab) H-1 H-2 12.5 12.5 84 84 1 1 0.5 0.5 0.5 0.5 0.5 0.5 1 1 q.s. q.s. 100 100
Selection of Superdisintegrants: In many orally disintegrating tablet technologies based on direct compression, the addition of superdisintegrants principally affects the rate of disintegration and hence dissolution. They are effective at lower concentration with greater disintegrating efficiency and mechanical strength. To formulate an effective orally disintegrating tablet which has optimum disintegration time and dissolution rate, the critical parameters that have to be taken into account are the choice of the superdisintegrants and optimization of the concentration of the superdisintegrant [31]. To assess the suitability of superdisintegrant various formulations were prepared as shown table 1.6 below.
Hydrochlorothiazide Galen IQ 720 Ac-Di-sol Crosspovidone Primojel Indion 414 PVP K-90
Formulation Code (mg/tab) H-3 H-4 12.5 12.5 83 83 1 1 1 1
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H-5 12.5 83 1 1
H-6 12.5 83 1 1
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Ingredients
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Table 1.6: Trials for selection superdisintegrant
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Magnesium stearate 0.5 0.5 0.5 0.5 Aerosil 0.5 0.5 0.5 0.5 Sodium saccharin 0.5 0.5 0.5 0.5 Mint powder 1 1 1 1 Brilliant green q.s. q.s. q.s. q.s. Total weight 100 100 100 100 To assess the suitability of concentration of superdisintegrants various formulations were prepared as shown in table1.7 below. Table 1.7: Trials for selection superdisintegrant concentration Ingredients
Formulation Code (mg/tab)
Hydrochlorothiazide
H-7 12.5
H-8 12.5
H-9 12.5
H-10 12.5
H-11 12.5
Galen IQ
83
82
81
80
79
Primojel
1
2
3
4
5
PVP K-90
1
1
1
1
1
Magnesium stearate
0.5
0.5
0.5
0.5
0.5
Aerosil
0.5
0.5
0.5
0.5
0.5
Sodium saccharin
0.5
0.5
0.5
0.5
0.5
Mint powder
1
1
1
1
1
Brilliant green
q.s.
q.s.
q.s.
q.s.
q.s.
Total weight
100
100
100
100
100
PREPARATION OF BILAYERED TABLETS OF METOPROLOL TARTRATE AND HYDROCHLOROTHIAZIDE: Optimized batch of MT (Batch M-8) and HCTZ (Batch H-7) was selected for formulation of bi-layered tablet. As previously reported procedure the granules of MT buccal mucoadhesive layer and blend of HCTZ orally disintegrating layer were prepared separately. Proposed design:
Step no 3: Compression of HCTZ orally disintegrating tablet (fig 1.1) After the backing membrane was compressed the blend prepared for compression of orally disintegrating tablet was properly weighed. The weight of the tablet decided was 100 mg. The tablet was then compressed on the layer of ethyl cellulose backing membrane.
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Step no 2: Application of backing membrane of Ethyl Cellulose (fig 1.0) For the application of the backing membrane, the buccal mucoadhesive tablets compressed on 8 mm flat beveled punch were then transferred to 9 mm die and a layer of EC was then compressed on it. The quantity of ethyl cellulose finalized was 50 mg.
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Fig no 1.3 Bilayered tablet of MT and HCTZ Procedure: Step no 1: Compression of MT Buccal mucoadhesive tablet (fig 1.0) The granules ready for compression were properly weighed and then compressed on single punch compression machine on 8 mm flat beveled punches. The weight of the tablet decided was 150 mg.
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Step no 4: Evaluation The final tablets were evaluated by separating both layers of bi-layered tablet and evaluating them individually as per the procedures given below. B) Evaluation a) Metoprolol tartrate buccal mucoadhesive tablets: The tablets were evaluated for physical strength, appearance, uniformity of thickness, hardness. Other important evaluations done were as follows, Mucoadhesive Strength: The mucoadhesive strength was checked using modified balance test. Porcine buccal mucosa was used as the model membrane. The mucosa was kept frozen in phosphate buffer pH 7.4 and thawed to room temperature before use. The mucosal membrane was excised by removing the underlying connective and adipose tissue and was equilibrated at 37 + 1.0 °C for 30 mins in phosphate buffer pH 7.4 before mucoadhesion strength evaluation. The tablet was stuck to the Teflon arm using cyanoacrylate adhesive and lowered into the mucosa under a constant weight of 5 g for a total contact period of 1 min. Mucoadhesion strength was assessed in terms of weight (g) required to detach the tablet from the membrane [32]. Surface pH: The method used to determine the surface pH of the formulation was similar to that used by Bottenberg et al [33]. A combined glass electrode was used for the purpose. The tablets were allowed to swell by keeping them in contact with 1 ml of distilled water for 2 hrs and pH was noted by bringing the electrode in contact with the surface of tablet and allowing it to equilibrate for 1 min. In-vitro dissolution studies: The Indian Pharmacopoeia Apparatus I was used to study the drug release from the buccal tablets. The dissolution medium consisted of 900 mL of phosphate buffer pH6.8. The study was performed at 37 ± 0.5 o C, with rotational speed of 50 rpm for a period of 45 mins. To study the drug release from only one side, the tablets were stuck to the paddle with ethyl cellulose layer facing to paddle. A sample (5 mL) was withdrawn at the end of test duration. The sample removed was filtered, diluted and analyzed at 275 nm using UV-Vis spectrophotometer [34]. Ex-vivo drug permeation: Preparation of porcine buccal tissue [35]: The mucosal membrane was excised by removing the underlying connective and adipose tissue of freshly slaughtered pig and was equilibrated at 37 + 1.0 °C for 30 mins in phosphate buffer pH 7.4. The buccal epithelium was carefully mounted in between the two compartments of Modified Franz Diffusion Cell. Tablets were stuck to the mucosa in the donor side containing 4mL simulated saliva pH 6.8. Receiver medium was 20 ml of phosphate buffer pH 7.4, mimicking the blood pH maintained at 37 ± 0.5 0C under gentle stirring. From the receiver compartment, 2 mL aliquots were collected at predetermined time intervals and replaced by an amount of fresh buffer. The test was performed for duration of 120 minutes. The sample removed was filtered, diluted and analyzed at 275 nm using UV-Visible spectrophotometer. Assay: Weigh and powder 20 tablets. Weigh accurately a quantity of the powder containing about 0.12 g of metoprolol tartrate, transfer to a 100-ml volumetric flask, add about 75 ml of ethanol (95 per cent) and shake for 15 minutes. Dilute to volume with ethanol (95 per cent), mix and filter. Dilute 5.0 ml of the filtrate to 50.0 ml with ethanol (95 per cent). Measure the absorbance of the resulting solution at the maximum at about 275 nm. Calculate the content of (C 15H25NO3)2, C4H6O6 from the absorbance obtained by repeating the operation using Metoprolol tartrate RS in place of the substance under examination [34].
In vitro dissolution studies: The Indian Pharmacopoeia Apparatus I was used to study the drug release from the orally disintegrating tablets. The dissolution medium consisted of 900 mL of0.1 M HCl. The study was performed at 37 ± 0.5o C, with rotational speed of 100 rpm for a period of 45 mins. A sample (5 mL) was withdrawn at the end of test duration. The sample removed was filtered, diluted and analyzed at 272 nm using UV-Vis spectrophotometer [38].
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Wetting time: The test was performed by five circular filter papers of 5-cm diameter which were placed in each of the five petri dishes with a 5-cm diameter. Then 5 ml of eosin solution, a water-soluble dye, was added to the petri dish. A tablet was carefully placed on the surface of filter paper. The time required for water to reach the upper surface of the tablets was noted as the wetting time [37].
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b) Hydrochlorothiazide orally disintegrating tablets: The tablets were evaluated for hardness and uniformity of thickness. The other important evaluations done were as follows, In vitro disintegration time: In vitro disintegration time was determined visually in a glass dish of 25ml distilled water with swirling every 10 sec. The disintegration time is the time when the tablet breaks or disintegrates completely [36].
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Assay: Weigh and powder 20 tablets. Weigh accurately a quantity of the powder containing about 20 mg of Hydrochlorothiazide, add 50 ml of 0.1 M sodium hydroxide, shake for 20 minutes and dilute to 100 ml with 0.1 M sodium hydroxide. Mix, filter, dilute 5.0 ml of the filtrate to 100 ml with water and measure the absorbance of the resulting solution at the maximum at about 273 nm (2.4.7). Calculate the content of C7H8ClN3O4S2 taking 520 as the specific absorbance at 273 nm [38]. RESULTS AND DISCUSSION: A) Formulation Development: 1) Buccal mucoadhesive tablets of Metoprolol tartrate: Recommended Dose of Metoprolol tartrate for the control of hypertension is 100 mg daily. The dose selected to formulate the buccal mucoadhesive tablet of MT was 50 mg twice a day. A Preformulation study made it evident that Metoprolol tartrate had poor flow characteristics hence, granulation technique was necessary prior to compression. Lactose was used as the diluent because lactose has an advantage of being a bland diluent and it thus prevents salivation and swallowing of drug [39]. Various mucoadhesive polymers like SCMC, Sodium Alginate, Guar Gum, HPMC K15M, Carbopol 974P and Polycarbophil AA1 were tried to achieve the desired mucoadhesion strength and drug release profile. The log P value of MT is just 0.5 [20] hence various permeation enhancers such as SLS and bile salts were tried to improve the permeability of the drug through the buccal mucosa. The main aim was to develop a buccal mucoadhesive tablet having a hardness of 2.5-3.5 Kg/cm2 and mucoadhesive strength 10 - 12 kg/cm2. The tablets compressed from the blend M-1 to M-6 were evaluated for various parameters and the results of all the parameters are given in the table 1.8 below, Table 1.8: Results of evaluation of mucoadhesive tablet layer of MT Code
Appearance
Integrity
Hardness (Kg/cm2)
Thickness (mm)
Mucoadhesion strength (Kg/cm2) 11 7 11 6.5 10 12
Surface pH
(%) Drug Release
Backing Membrane: For the delivery of MT, bilayered design (drug containing mucoadhesive layer and backing layer) was selected for following reasons, It prevents the contact of bitter MT with taste receptors.
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Ex-vivo Permeation Studies: Batches M-7 to M-9 made using SLS as the penetration enhancer showed a good increase in the amount of drug permeated. Batch M-7 showed 199.27% increase and batches M-8& M-9 containing 2 and 3 % SLS respectively showed 250.72 % & 257.97 % increase respectively as compared to that of plain drug. Batches formulated using Bile salts as the penetration enhancer though showed an increase in the amount of drug permeated as compared to the plain drug but the release achieved was lower than that achieved by using SLS. Hence, penetration enhancer SLS (2% w/w) was selected to bring about an increase in Ex-vivo permeation of Metoprolol tartrate by 250% as compared to that of the pure drug.
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M-1 +++ +++ 3.1 2.5 6 83.12 % M-2 ++ ++ 1.7 2.4 6 67.11 % M-3 +++ +++ 2.9 2.4 7 79.17 % M-4 + + 1.5 2.5 6 51.34 % M-5 ++ ++ 2.5 2.5 6 59.13 % M-6 +++ +++ 3.1 2.5 7 97.63 % + Poor ++ Acceptable +++ Good Not acceptable Batch M-1 made with Carbopol 974P and Batch M-3 made with Polycarbophil AA1 showed good mucoadhesion strength, hardness and showed average in-vitro drug release. Batch M-2 made with HPMC K15M showed poor mucoadhesion strength, hardness and also poor in-vitro drug release. Batch M-4 made with sodium alginate gave very poor tablet integrity and appearance. Tablet formulated showed very poor mucoadhesion strength, hardness and poor in-vitro drug release. Batch M-5 made using guar gum showed good mucoadhesion strength and hardness. Guar gum on exposure to dissolution fluids hydrated and formed a viscous gel layer that slowed down further seeping-in of dissolution fluids towards the core of the tablet. Therefore the in-vitro drug release was poor. Batch M-6 made using SCMC good mucoadhesion strength and hardness. The in-vitro drug release was also found to be very good. From the above results it was evident that the batch M-6 which had SCMC as the mucoadhesive polymer and PVP K-30 as the binder showed a good balance between mucoadhesion strength and hardness. The surface pH of the tablet was found to be neutral and hence it would not irritate the buccal mucosa. Also the in-vitro drug release was very good. SCMC is an anionic polymer having good mucoadhesion strength [40]. The batch M-6 was further used to assess the permeation enhancers and also for determining the quantity of GRC of ethyl cellulose required to give an efficient backing membrane.
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It allows unidirectional drug release and avoids loss of drug by swallowing with saliva. It maintains sufficient concentration gradient of MT at buccal mucosa for the permeation. For the application of the backing membrane, tablets of batch M-8 which were compressed on 8 mm flat beveled punch were then transferred to 9 mm die and a layer of GRC of ethyl cellulose was then compressed on it. It was evident from the trials conducted that the batch M-15 which had 50 mg of GRC of ethyl cellulose provided efficient backing membrane to the tablet. It effectively covered the entire back and side surfaces of the tablet and provided unidirectional flow of the drug and hence could prevent the drug loss and inconvenience to the patients due to bitter taste. The final evaluation results of the mucoadhesive layer are as shown in table 1.8. Table 1.8: Results of evaluation of buccal mucoadhesive layer of metoprolol tartrate. MT Buccal Mucoadhesive tablet layer(M-15) Parameter Result Appearance Good Average weight 180.06 0.27 mg Hardness 3.1 0.02 kg/cm2 Thickness 2.5 0.03 mm Mucoadhesion strength 12.03 0.15 kg/cm2 Surface pH 7 % drug release 97.76 0.43 Assay 95.43 % The buccal mucoadhesive tablets of MT were prepared using Lactose as the diluent and different mucoadhesive polymers like SCMC, Sodium Alginate, Guar Gum, HPMC K15M, Carbopol 974P and Polycarbophil AA1. All the batches were prepared by granulation followed by compression method with the single punch tablet compression machine using 8 mm flat punch. It was evident with the developed formulations, that the MT release and bioadhesion properties of buccal tablets can be controlled by changing the polymer type and concentration. Mucoadhesive strength, hardness and drug release were taken as the basis to optimize the buccal mucoadhesive tablets. Prepared tablets were evaluated for appearance, integrity, hardness, thickness, mucoadhesion strength, surface pH, drug release and ex-vivo permeation release. It was evident that the combination of lactose as the diluent, SCMC as the mucoadhesive polymer, PVP K-30 as a binding agent, SLS as penetration enhancer and ethyl cellulose as the backing membrane gave a good balance between mucoadhesion strength, surface pH, drug release and drug permeation and also provided optimum hardness and robustness. The tablets prepared had hardness of 2.5-3.5 Kg/cm2 and mucoadhesive strength 10 - 12 kg/cm2 and optimum drug release. Formulation M-8 was therefore selected as it showed most promising results. It was thus evident that development of buccal mucoadhesive tablet of Metoprolol tartrate was one of the alternative routes of administration to avoid first‐pass effect and to improve the bioavailability of Metoprolol tartrate through buccal mucosa and enhance the release of drug for extended period of time. In addition, the formulation reduces the need of frequent administration and enhances patient compliance. Thus it can be concluded that the Metoprolol tartrate tablets have a strong potential for use as a mucoadhesive buccal delivery system. 2) Orally disintegrating layer of Hydrochlorothiazide Recommended Dose of Hydrochlorothiazide for the control of hypertension is 25 mg daily. The dose selected to formulate the orally disintegrating tablet of HCTZ was 12.5 mg to be given twice daily. Flow properties of the blend H-1 and H-2 to assess the suitability of the diluents are shown in the table 1.9 below, Table 1.9: Result of evaluation of flow properties of blend for the assessment of diluents
No. 1. 2.
Test Disintegration time Wetting time
H-1 25 secs 22 secs
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H-2 32 secs 26 secs
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Table 2.0: Result of evaluation of tablets for the assessment of diluents
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No. Test H-1 H-2 1. Untapped bulk density 0.198 gm/ml 0.203 gm/ml 2. Tapped bulk density 0.25 gm/ml 0.28 gm/ml 3. Compressibility 20.8 % 27.5 % 4. Angle of Repose 25.73° 30.73° 5. Flow Rate 1 g/60 secs 1 g/60 secs Evaluation of the tablets prepared from the blend H-1 and H-2 are shown in table 2.0 given below,
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The evaluation of flow properties of H-1 and H-2 indicated that the blend prepared by using Galen IQ 720 as the diluent had better flow properties and flow rate. Also the tablets prepared from the blend H-1 had optimum disintegration time and wetting time as compared to the tablets prepared from the blend H-2. Hence Galen IQ 720 was selected as the diluent. Choosing Galen IQ 720 as the diluent also offers added advantage of having a good mouth-feel because of its pleasant sugar like natural sweet taste [41]. Further from the trials conducted, it was evident that the batches of tablets prepared from the blend H-1 and H-2 lacked sufficient hardness and robustness. Thus PVP K-90 was used as a binding agent to give a robust ODT which disintegrates in vitro within 30 seconds. The tablets compressed from the blend H-3 to H-6 were evaluated for various parameters and the results of all the parameters are given in the table 2.1 below, Table 2.1: Result of trials for selection of diluent and superdisintegrant Formulation code
Average weight (mg)
Hardness (Kg/cm2)
Thickness (mm)
H-3 H-4 H-5 H-6
100.130.23 100.400.12 100.150.01 100.570.98
1.4 1.5 1.4 1.2
2.5 2.2 2.4 2.5
In Disintegration (sec) 25 30 20 27
vitro time
Wetting time (sec) 18 21 14 20
Drug Content (%) 100.68 101.12 100.15 100.43
As shown in the table 2.1it was evident from the batches H-3 to H-6, that the combination of Galen IQ 720 as the diluent, Primojel as the superdisintegrant and PVP K-90 as a binding agent gave a good balance between in vitro disintegration time, wetting time and also provided optimum hardness and robustness. The best results were given by the batch H-5 and hence it was used for further evaluation and optimization. Table 2.2: Result of trials for selection superdisintegrant concentration Formulation code
Average weight (mg)
Hardness (Kg/cm2)
Thickness (mm)
H-7 H-8 H-9 H-10 H-11
100.340.54 100.130.68 100.450.12 100.090.05 100.210.16
1.3 1.4 1.5 1.3 1.4
2.2 2.1 2.3 2.2 2.1
In vitro Disintegration time (sec) 20 18 22 17 19
Wetting time (sec) 15 14 16 13 16
Drug Content (%) 100.26 100.20 101.01 100.12 101.03
As shown in the table 2.2 the batches H-7 to H-11 indicate that increase in the concentration of Primojel superdisintegrant did not have any appreciable effect on the disintegration time. Thus the concentration of Primojel was fixed at 1 % w/w. The evaluation of the final selected batch was carried out and the results are as given in table 2.3. Table 2.3: Results of evaluation of orodispersible layer of hydrochlorothiazide.
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The orally disintegrating tablets of Hydrochlorothiazide were prepared using Galen IQ 720 and Pharmatose DCL 11 as the diluent and different concentrations of the superdisintegrants like Ac-Di-Sol, Primojel, Crosspovidone, and Indion 414. All the batches were prepared by direct compression method with the single punch tablet compression machine using 9 mm flat punch. Disintegration time and drug release were taken as the basis to optimize the orally disintegrating tablet. Prepared tablets were evaluated for thickness, hardness, uniformity of weight, disintegration time, wetting time and dissolution study. It was evident that the combination of Galen IQ 720 as the diluent, Primojel as the superdisintegrant and PVP K-90 as a binding agent gave a good balance between in vitro disintegration time, wetting time, drug release and also provided optimum hardness and robustness. The tablets prepared had disintegration time of less than 30 secs and 100% drug release. Formulation D1 was therefore selected as it showed most promising
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HCTZ Orally disintegrating tablet layer (H-7) Parameter Result Appearance Good Average weight 100.030.18 mg Hardness 1.3 0.03 kg/cm2 Thickness 2.2 0.07 mm In-vitro disintegration time 20 2 seconds Wetting time 15 3 seconds % drug release 98.56 0.59 Assay 98.32 %
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results. It was thus evident that development of orally disintegrating tablet of Hydrochlorothiazide was one of the alternative systems of administration to avoid inconvenience to geriatric patients and also to improve the bioavailability of Hydrochlorothiazide by rapidly disintegrating or dispersing in the saliva followed by immediate release of the drug which is accompanied by its dissolution and absorption. In addition the tablets can be administered without the need for water or chewing providing best remedy for patients suffering from dysphagia. Thus it is evident that the Hydrochlorothiazide has a strong potential to be formulated as orally disintegrating tablets. CONCLUSION:
Fig 1.4: Final tablets having white coloured orodispersible layer, blue coloured mucoadhesive layer with the red backing membrane
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The basic objective of the proposed work was to develop a formulation which comprised of combination of two drugs which had different modes of anti hypertensive action; but when they were combined together as a single unit they should provide synergistic effect for the control of hypertension. With this objective bilayered tablet (as seen in fig 1.4) was designed which comprised of buccal mucoadhesive layer for the effective delivery of Metoprolol tartrate and orally disintegrating layer for administering hydrochlorothiazide. The bilayered tablet can be administered anywhere and anytime without the need of water or chewing and thus quite suitable for geriatric population for whom the selected drugs are usually prescribed. It is also beneficial for non co-operative patients and also those who travel regularly and face a problem of water unavailability. It can also overcome the problems associated with dysphagia which usually leads to failure of therapy. The bilayered tablet ensures that MT can be administered in the form of buccal mucoadhesive tablet to overcome its significant first pass metabolism for better bioavailability and minimum side effects. Also the superdisintegrant based orally disintegrating tablet of HCTZ would provide quick onset of action without the need of water for swallowing thus providing better clinical performance and patient compliance. Thus the bilayered tablet has achieved the objective of effective control of hypertension with cost effectiveness, low dose, reduced frequency of administration, improved bioavailability and hence improved patient compliance and effective therapy. Thus it may be concluded that the bilayered tablet can be an ideal alternative for usually prescribed drug combinations with more than one unrelated pharmaceutical problem.
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