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1 6 DOXYCYCLINE GASTRO-RESISTANCE TABLETS 6.1 Aim of the Present Work Enteric coated/gastro-resistance tablets are solid unit dosage forms meant for oral administration and which are design in such a way that it by pass the gastric environment of stomach 1 and release the active the active content in the basic ph of small intestine. Doxycycline 2 is an universal antibiotic use to treat gram -ve infections where the susceptible organism was strongly proven to be present and also used to treat different microbial infections. It is an tetracycline antibiotic. Its half life is around 18 hours to 22 hours and its absorption is through the lower part of intestine. 3 ph of small intestine in different regions was found to be around 5 to 7 PH in duodenum, 6 to 7 PH in jejunum and 7 PH in ileum. Eudragit and Hypromellose phthalate polymers are selected where the dissolution properties are above ph 6.0 and ph 6.4 respectively. Polymers coating solution concentrations are designed to develop the targeting action of doxycycline in small intestine. There are numerous delayed release polymer available that are meant for protection of against the strong acid of gastric environment. 4,5,6,7 These delayed release polymer are dissolve at higher ph of intestine as it is soluble in the basic environment of intestine. Doxycycline is an universal antibiotic use for treatment against gram negative infections and where the susceptible organism was strongly proven to be present and also used to treat different microbial infections. Its half life is around 18 hours to 22 hours and most of the dose is absorbed through small intestine. 8 There are also some disadvantage associated with the standard formulation of doxycycline and that are gastrointestinal upset, that is not suitable for the patient, and thus does not give its desire pharmacological activity. 9 Anorexia, vomiting, nausea, enterocolitis, glossitis, diarrhea, dyspepsia and inflammotary lesions in anogenital region. In some case there is also disorder of of Hepatotoxicity. These is caused due to reaction by both oral and intravenous administration of tetracyclines. There are also some instances of esophagitis and esophagul ulcerations in some patients which had taken medicine. JJT University, Rajasthan Page 122

2 Enteric-coating/ delayed release are the dosage form in which the active content is coated with enteric coating polymer which is required for protection of the drug substance n the gastric environment. 10 These dosage form reduces the rate of irritation in stomach, rate of nausea and vomiting. 6.2 Objective:- Preparation and evaluation of gastric resistance / delayed release tablet of doxycycline based on enteric coating polymers that remains intact at gastric environment. To exercise different process variable and formulation variable which had effect on the release profile of the active content. Evaluation of different polymers which do not have any effect of gastric environment and dissolves / disintegrate fast in basic ph of intestine. 6.3 Principles to achieve goal Tablets should have satisfactory physical properties. Tablet release NMT 10 % w/w of drug content for two hrs in 1.2 ph Tablets release immediatly in 6.8 ph (previously exposed for two hours in 1.2 ph). JJT University, Rajasthan Page 123

3 6.4 Methodology Method of manufacturing enteric coated tablets Dry mix method Co-Sift Ingredient Doxycycline hydrochloride, Microcrystalline Cellulose (PH 102), Pregelatinized Maize Starch (Starch 1500), Colloidal Anhydrous Silica through 40 #. Mix the above sifted material in blender (25 liters) at twenty four RPM for five minutes. Further sift magnesium stearate through 40 # and mix the sifted magnesium stearate with above blend in blender (25 liters) for five minutes at twenty four RPM. Compression Dry Mix was done as per above mentioned process and the formulation and then compression was performed on 10 station tablets press.(make : Cadmach, INDIA). Punch size : 8.73 mm Shape : Round and biconvex The Composition of Doxycycline HCl are mentioned in Table 1 PREFORMULATION STUDIES 11 Angle of repose It is used for indirect methods to check the flow property of the powder. It had large impact on the physical attributes of the dosage form. It can be calculated as Angle of repose = tan 1h/r h stands for height r stands for radius Bulk density 12 Bulk density is measured by mass divided by the volume. Where mass is mass of powder and volume is volume occupied by powder Pb = (M/V) g /cc Bulk density depends mainly on the density of particle, adherence property of the particle, size of particle, shape of particle etc. JJT University, Rajasthan Page 124

4 Tapped density It is the ratio of mass and volume. It is performed as weigh the sample and transfer the same to the specified cylinder and place the same on the tapped density apparatus and was operated as per decided no. of taps. Tapped density = mass / volume (tapped volume) Carr's Index It had been calculated as % Compressibility = Tap density Bulk density / Tap density x 100 Hausner's ratio It had been calculated as Hausner s ratio = Tap density / bulk density Physical evaluation of core tablets Hardness test 13 Dr.Scheluenger s hardness tester were employed for measurement of hardness of tablets. Thickness and diameter These parameters of the tablets were noted during the compression process by using vernier caliper. Friability It was determined in VEEGO tablets Friabilator. Weight variation The tablets were selected randomly and the weight of the same were checked and noted. Disintegration test 14 Dosage form were kept in the apparatus and placed in one liter beaker and the time taken to disintegrate the tablets were evaluated. JJT University, Rajasthan Page 125

5 Preparation of enteric coated tablets The compressed tablets of the doxycycline were coated with different delayed release of enteric coating polymers like hypromellose phthalate, Eudragit L30D55, acryl EZE and cellulose acetate phthalate. Composition of Doxycycline hydrochloride gastro resistance tablets are given in mentioned table. Drug content 15 Weight and powder ten tablets. From the above powder weigh powder equivalent to 100 mg of doxycycline hydrochloride and the same were dissolved in ph 6.8 phosphate buffer. Different concentrations of drug were prepared and analyzed spectrophotometrically (UV 1700 Shimadzu Corporation, Japan). INVITRO DISSOLUTION TEST The release of active content form the pharmaceutical dosage form was done in dissolution test apparatus. Apparatus : Paddle RPM : 100 Time points : two hours in acidic media i.e. 0.1 N HCl Followed by phosphate buffer ph 6.8 for 45 minutes Dissolution performed as per US Pharmacopoeia. The analysis was done in UV spectrophotometer. The absorbance was measeured at 352 nm and % drug dissolved was calculated. Table 6.1: Formulation of Doxycycline HCl enteric coated tablets (core) Sr. No. Ingredients Theoretical Qty/tab (mg) Batch No. D 1. Doxycycline hydrochloride Microcrystalline Cellulose (PH 102) Pregelatinized Maize Starch (Starch 1500) Colloidal Anhydrous Silica Magnesium Stearate Total (Average weight) JJT University, Rajasthan Page 126

6 Table 6.2: Coating solution materials (enteric coating) B.No. D 1 D 2 D 3 D 4 D 5 D 6 D 7 D 8 Sr.No. Weight gain 5 % w/w 9 % w/w 1 Eudragit L 30 D Hypromellose 2 phthalate Cellulose acetate phthalate Acryl eze Triethyl citrate Pu. talc Isopropylalcohol - Q.S. Q.S. - - Q.S. Q.S. - 8 Dichloromethane - Q.S. Q.S. - - Q.S. Q.S. - 9 Pu. water Q.S. - - Q.S. Q.S. - - Q.S. Table 6.3 Physical parameters Sr.No. Test Result 1 Angle of repose Bulk density (gm/ml) Tap density (gm/ml) Carr s index Hasner's Ratio 1.43 JJT University, Rajasthan Page 127

7 Table 6.4 Core tablet evaluation Sr.No. Test Result 1 Weight variation 245 mg 256 mg 2 Average weight 251 mg 3 Hardness 90 N (70 N 110 N) 4 Thickness 4.25 mm (4.20 mm 4.31 mm) 5 Diameter 8.73 mm (8.72 mm 8.74 mm) 6 Friability % w/w 7 Disintegration test 3 minutes to 7 minutes 8 Drug content 99.6 % Table 6.5 Dissolution profile comparision (enteric coated tablet) Acid stage Media (0.1 N HCl) Buffer stage (ph 6.8 phosphate buffer) Times ( minutes) B.No. % Cumulative drug dissolved D D D D D D D D JJT University, Rajasthan Page 128

8 Dissolution profile comparision ph 6.8 phosphate buffer % cumulative drug dissolve times in minutes D5 Doxycycline HCl delayed release tablets D6 Doxycycline HCl delayed release tablets D7 Doxycycline HCl delayed release tablets D8 Doxycycline HCl delayed release tablets Figure 19 Dissolution profile comparision 6.5 Results and discussion Several technologies have been used in the development of enteric coated / delayed tablets and in the preset investigation enteric coated tablets of Doxycycline were prepared by Dry mix technique then compression followed by enteric coating. The various physical property of powder like its flow property. When there is measurement of an angle of repose a flow property of powder can be known its mixing and the property of powder and its effect on the compression. 17 The angle of repose was found to be between 22 to 27 of all the evaluated blend. The Hausner s ratio of blend evaluated was aroung 1.43 and compressibility comes around 30 %. So by reviewing the data it shows good flow properties. The precompression parameters were evaluated and found well within the specified limit. The compression parametes were satisfactory as shown in table 4. The compaction force of the tablets is between 70 N to 100 N which is showing good mechanical strength. When the tablets were subjected in friability test apparatus for friability it results in to less than 1 % w/w. The weight variation is also under control. Assay of the enteric coated tablets was found in between 90 % to 110 % and shown in table.the disintegration time of the dosage form are also well within the specified limit as per pharmaceutical compendium. In the present study there are four different enteric coated polymer used and i.e. cellulose acetate phthalate, Eudragit L 30 D 55, Hypromellose phthalate, Acryl EZE. These enteric JJT University, Rajasthan Page 129

9 coating polymer are insoluble in gastric environment. For enteric coating of these polymer for tackiness of the enteric coating film talc is required and for plasticity suitable plasticizer like triethyl citrate is required. 18 By addition of talc and triethyl citrate it gives good physical attributes and process suitability. 5 % w/w of enteric coating weight gain of different formulation were evaluated with different enteric coating material. The enteric coated tablets were analysed and results were shown in table 6.5. The 5 % w/w enteric coated formulation failed in the disintegration test when exposed to acidic media at ph 1.2. So, for protection of the formulation in this media more coating is required and formulated four more formulation with 9 % w/w i.e. greater weight gain %. The 9 % weight gain tablets when exposed to acidic environment it does not shown any rupture of film or dissolution of the film and gave protection to core against the acidic nature and the result were tabulated in table ,20 Drug release profile was done to check the impact of polymer and its concentration on the integrity of the enteric coating film. Dissolution profile was performed on 9 % w/w weight gain of formulation i.e. D4 to D8 in the acidic media for two hours following ph 6.8 phosphate buffer for 45 minutes. The tablets with 9 % w/w weight gain shows good and satisfactory physical and chemical attributes. It protect the dosage form up to two hours in the acidic environment and dissolve in ph 6.8 phosphate buffer in 45 minutes. 21,22,23 JJT University, Rajasthan Page 130

10 6.6 Conclusion In the current study doxycycline gastro resistance tablets were formulated utilizing polymer i.e. Hypromellose phthalate, cellulose acetate phthalate, Acryl EZE and Eudragit L 30 D 55 to acquire five percent w/w weight gain. During evaluation these tablets fails in the test against acid as the film is rupture in acidic media and dosage form comes in contact with acidic media. But when enteric coating of the film with same enteric coating polymer to 9 % w/w coating the tablets does not show any change in integrity of the filmwhen exposed to acidic media. By looking here dissolution profile of same tablets in alkaline media ph 6.8 phosphate buffer the formulation with Batch No. D5 and D8 coating layer dissolve faster then the formulation with Batch No. D6 and D7. The formulation with Batch No. D5 and D8 containing Eudragit L 30 D 55 shows better results compare to the formulation containing Hypromellose phthalate and cellulose acetate phthalate. Formulation with Batch No. D5 and D8 shows intactness in the acidic environment and dissolve rapidly in the buffer stage at ph 6.8 phosphate buffer. JJT University, Rajasthan Page 131

11 6.7 REFERENCES: 1) Lachman L., Herbert A, Liberman, Kaing JL.. The theory and practice of industrial pharmacy, Varghese publishing house, Bombay, 3rd edition, ) Seth.S.D. Text book of Pharmacology, 1999; 2nd edition, ) / wiki / Doxycycline. 4) Murthy KS, Kubert DA, Fawzi MB. In vitro release characteristics of hard shell capsule products coated with aqueous - and organic-based enteric polymers, Journal of biomaterial application. 1988; 3: ) Sinha VR, Kumria R. Coating polymers for colon specific drug delivery: A comparative in vitro evaluation, Acta Pharmaceutica Sinica B. 2003; 53: ) Marvola M, Nykänen P, Rautio S et al. Enteric polymers as binders and coating materials in multiple-unit site-specific drug delivery systems, European Journal of Pharmaceutical science. 1999; 7: ) Nesbitt RU, Goodhart FW, Gordon RH. Evaluation of polyvinyl acetate phthalate as an enteric coating material, International Journal of Pharmaceutics. 1985; 26: ) Chakraborty S., Sarkar S. and Debnath SK., Formulation Development and Evaluation of Pantoprazole Enteric Coated Tablets, International Journal of ChemTech Research. 2009;Vol.1, No.3, July-Sept, pp ) Bryant SG, Fisher S, Kluge RM. Increased frequency of doxycycline side effects, Pharmacotherapy. 1987;7(4): ) Wolffe JB. What value enteric coating. American journal of Medicine, 1948; Jul;5(1): ) Jaimini M, Rana AC, Tanwar YS. Formulation and Evaluation of Famotidine Floating Tablets, Current Drug Delivery 2007, 4, ) Reddy LH, Ghose B, Rajneesh, Fast dissolving drug dlivery system, A review of Literature, Indian Journal of Pharmaceutical Science, 1997; 59(4), JJT University, Rajasthan Page 132

12 13) Sreenivas SA, Gadad AP. Formulations &Evaluation of ondansetron HCL directly compressed mouth disintegrating tablets, Indian drugs, 2006; 43(1), ) Ziyaur R, Mushir A, Khar RK, Design and Evaluation of bilayer floating tablets of captopri l, Acta Pharmaceutica Sinica B, 2006; 56, ) Rockville MD, USP, 27th revision, USP convention Inc 2004; ) USP XXIV, 17th Ed., Rockville, 1947; MD ) Abdelbary G, Eouani C, Prinrerre P, Joachim J, Reynier JP, Piccerelle PH. Determination of the invitro Disintegration profile of Rapidly Disintegrating tablets and Correlation with Oral Disinteration, International journal of Pharmaceutics 2004 ; 292 ; ) Crotts G, Sheth A, Twist J et al. Development of an enteric coating formulation and process for tablets primarily composed of a highly water-soluble, organic acid, European Journal of Pharmaceutics and bio pharmaceutics. 2001; 51: ) Felton LA, Haase MM, Shah NH, et al. Physical and enteric properties of soft gelatin capsules coated with eudragit L 30 D-55, 1995; 113: ) El-Malah Y, Nazzal S. Novel use of Eudragit NE 30D/Eudragit L 30D- 55 blends as functional coating materials in time-delayed drug release applications, International Journal of Pharmaceutics. 2008; 357: ) Sauer D, Watts AB, Coots LB, et al. "Influence of polymeric subcoats on the drug release properties of tablets powder-coated with pre-plasticized Eudragit L , International Journal of Pharmaceutics. 2009; 367: ) Wei G, Knoch A, Laicher A, et al. Simple coacervation of hydroxypropyl methylcellulose phthalate (HPMCP) II. Microencapsulation of ibuprofen, International Journal of Pharmaceutics. 1995; 124: ) Kim H, Park JH, Cheong W et al. Swelling and drug release behavior of tablets coated with aqueous hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles, Journal of Control Release 2003; 89: JJT University, Rajasthan Page 133