Title of Invention

PROCESS OF PREPARATION OF MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS OF CEFADROXIL AND CEPHALEXIN

Abstract

1. A modified release pharmaceutical compositions in the form of a tablet coated with a water soluble polymeric film comprising cefadroxil, or cephalexin or their pharmaceutically acceptable hydrates, salts or esters as an active ingredient in an amount ranging from 50% to 90%, a hydrophilic polymer hydroxy propyl methyl cellulose (HPMC) in an amount ranging from 2- 20 %, more preferably from 5 % to 8 % by weight of the total composition and a water soluble or water dispersible diluent.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Modified release pharmaceutical compositions of cefadroxil and cephalexin"" 2. APPLICANT (a) NAME: M/S. LYKA LABS LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: Gopakumar Nair Associates, Nair Baug, Akurli Road, Kandivli (East), Mumbai - 400 101, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it has to be performed. ORIGINAL 652/MUM/02 2 Field of the Invention: The present invention relates to a modified release pharmaceutical compositions comprising the Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters as an active ingredient and a hydrophilic polymer of the HPMC (hydroxy propyl methylcellulose) group as extend release polymer. The present invention also relates to process for preparing an orally administrable pharmaceutical dosage form comprising the modified release pharmaceutical composition. Background of the Invention: Cefadroxil and Cephalexin are semisynthetic cephalosporin antibiotics available in the form of tablets or granules for oral suspension that require to be taken three or four times a day. The recommended daily dose of Cefadroxil ranges from 500 mg to 1000 mg per day and that of Cephalexin ranges from 750 mg to 1050 mg per day depending on the severity of infection. As per prior art the composition of modified release is directed towards increasing the bioavailability of active ingredient so that it is bioequivalent with immediate release formulation. The modified release tablets maintain effective plasma levels throughout the day, improving therapeutic efficacy and reducing the frequency of dosing thus making the therapeutic regimen more convenient and patient friendly. The use of hydrophilic polymers such as medium to high viscosity grade Hydroxy Propyl Methyl Cellulose to produce modified release pharmaceutical compositions is known in the prior art as hydrogel technology. The polymer swells when it comes in contact with aqueous fluid to form a "soft mucilaginous gel" barrier on the surface of the tablet. This surface layer slows the release of the drug from the matrix. As the surface layer erodes with time, the drug is released slowly over an extended period of time. So the release of drug from matrix is controlled primarily by diffusion of the drug, or by surface erosion of the hydrophilic polymers into the surrounding medium, or a combination of the two processes. The release profile represents a balance between swelling and slow erosion of polymer. 3 As per prior art the modified release tablet compositions were formulated in such a way that, on oral ingestion it will attain a maximum peak plasma concentration at statistically significant lower values as compared to that produced by an immediate release composition and thereby reduce possible adverse reactions. Generally, the composition is directed towards improving bioavailability of active so that it is bioequivalent with immediate release, which is taken 3 to 4 times a day. The formulation thus provides for constant blood levels of active ingredient for an extended period thus decreasing frequency of administration, thereby improving patient compliance to the dosage regimen. A number of drug delivery systems aimed at controlling release rate of Cefadroxil and Cephalexin are known in prior art. However, they suffer from a number of disadvantages as described below. US 5948440 describes a sustained release matrix formulation for Cefaclor and Cephalexin comprising of 50 - 90 % drug, 5-35 % of hydrophilic polymers that is Medium viscosity grade HPMC (Methocel K4M CR) 0.1-20 % and 0.1 to 20 % of HPC that is (Hydroxy Propyl Cellulose). The process describes compaction / slugging using roll compactor. As a disadvantage however a large amount of heat is generated during this process which can lead to degradation of antibiotics like Cefaclor / Cephalexin. Also in order to impart adequate compressibility to the blend an additional excipient L-HPC (low substituted hydroxy propyl cellulose) is required which increases the cost of the formulation. US 4369172 describes a sustained release matrix formulation for Cefaclor and Cephalexin comprising of HPMC alone or in combination with ethylcellulose and /or sodium carboxy methyl cellulose. The HPMC employed is of a medium viscosity grade (4000 centipoise) that is Methocel 60 HG E4M, Methocel 90 HG K15M, Methocel 90 HG K4M and the method employs direct compression. Disadvantages include utilization of a large proportion of the sustaining polymer (upto 30 %) and possible degradation of drug due to direct compression which employs higher compression force leading to generation of heat. 4 US 4250166 describes a long acting Cephalexin formulation comprising of rapid and slow releasing components. It utilizes coated particulate Cephalexin, coated with a mixture of methylmethacrylate and methacrylic acid for sustaining release. It however employs expensive coating equipment which is as an obvious drawback. US 4968508 describes a prolonged release Cephalexin formulation comprising of 5-29% of HPMC and 0.5 % to 25 % of acrylic polymer (Eudragit L-100-55). The drawback here is the employment of an expensive additional ingredient. OBJECTS AND ADVANTAGES OF THE INVENTION: The objects and advantages of the present invention are given below as follows:-The present invention provides a modified release pharmaceutical compositions comprising the active ingredient Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters, provided for extended release of the drug, thus giving more uniform blood levels of the drug in human subjects; thus reducing the frequency of dosing making the therapeutic regimen more effective and patient friendly compared to immediate release formulation. The present invention also provides a process for preparation of the modified release pharmaceutical compositions. The present invention employs 2-20% of a low to medium viscosity grade HPMC (50 to 4000 centipoise) singly. It effectively uses one hydrophilic polymer that is HPMC unlike the patents in question, which utilizes a combination of two such hydrophilic polymers or additional controlled release excipients. The extended release profile is achieved using a low concentration of a low viscosity grade HPMC. The present invention thus scores over the mentioned patents in terms of utilization of sustaining polymer. The present invention utilizes wet granulation process for preparation of granules. The granulation and drying process are optimized to impart minimum moisture and heat to the blend and thus prevent degradation or loss of potency of active ingredient. The method is thus simple, conventional and eliminates the use of expensive equipment like roll compactor and hence is more cost effective. 5 Also since the present invention involves granulation followed by compression, it employs a lower compression force compared to direct compression, therefore less heat is generated during compression. This ensures better stability of the drug. Moreover the final tablets obtained show better hardness and lower friability compared to those prepared by direct compression as in prior art. The granulation and drying processes are so optimized to minimize exposure of drug to moisture and heat; the critical factors affecting stability of the drug during processing. The drying temperature and time are so optimized to ensure minimum exposure of the drug to high temperature. This ensures better stability of the drug and the final formulation during the processing stage itself; a superior alternative to slugging which is known to generate large amount of heat. To summarise, it effectively utilizes a single hydrophilic polymer and eliminates the need for any other expensive excipient or equipment unlike prior art. It makes use of the granulation process that is simple and convenient and does not demand expensive equipment or skilled labour. These attributes make the formulation more cost effective. Other objects and advantages of the invention are as follows:-The tablets are compressed to either circular or capsule shape to facilitate uniform coating during the film coating procedure. These shapes impart the property of smooth rolling in the coating pan which further facilitates uniform spreading and film formation. It employs a rapidly dissolving derivatized cellulosic polymeric film coat which provides sufficient stability to the final formulation (core tablets) from moisture and heat, at the same time disintegrating fast enough not to hinder release of drug from matrix. The compressibility of the blend obtained is conveniently high to give tablets of hardness ranging from 3 to 12 kg/sq. cm with minimum force of compression. This ensures minimum heat generation and hence preventing degradation of drug during compression. This ensures that the core tablets obtained are of an acceptable white to off white colour unlike the pale yellow tablets obtained when high heat is 6 generated during compression. The process thus adds aesthetic value to the formulation. The final tablets obtained exhibit greater stability, lower friability and a consistent extended release pattern. Further objects and advantages of the present invention will become apparent from a consideration of the ensuing description. DETAILED DESCRD7TION OF THE INVENTION: The modified release pharmaceutical compositions of this invention is in the form of a matrix tablet comprising the active ingredient, hydrophilic polymer, water soluble or water dispersible diluent and other pharmaceutically acceptable excipients like water soluble diluents, lubricants and glidants. The core tablets may further be coated with a rapidly dissolving polymeric film coat. According to the present invention, the pharmaceutical compositions comprises Cephalosporin antibiotics for example Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient. The active ingredient may be present in an amount from about 50 - 90 % by weight, more preferably from about 60 - 85 % by weight of the total weight of the pharmaceutical composition. Further, the active ingredient for example Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters may be present in an amount from 250 to 1500 mg per tablet. According to the present invention, the pharmaceutical composition comprises of a hydrophilic polymer of derivatised cellulosic polymer group as the release-sustaining polymer. For the purpose of this patent the polymer is selected from the group of low (less than 1000 centipoise) to medium viscosity (from 1000 to 10000 centipoise) grade Hydroxy Propyl Methyl Celluloses. For the purpose of this patent, the polymer has a viscosity of 50 centipoise to 4000 centipoise, more preferably 100 centipoise to 500 centipoise. The polymer is employed alone effectively in the present pharmaceutical compositions to achieve required release profile. 7 The HPMC (Hydroxy Propyl Methyl Cellulose ) used in the case of this patent is of the grade Metolose 90 SH 100 manufactured by Shin-Etsu Chemical Co., Japan having viscosity 100 centipoise; a methoxyl content of 19-24 % and a hydroxy propyl content of 4 -12 %. It may be present in this formulation in an amount ranging from about 2- 20 % of the composition by weight, more preferably from 5-8 % by weight of the total composition. According to the present invention the pharmaceutical compositions comprises of one or more of water soluble or water dispersible diluent which is used as diluent or filler to increase the bulk of tablet and to improve compressibility. A water soluble / dispersible diluent is selected since it disperses readily in water without posing a hindrance to release of drug from matrix. For the purpose of this invention the water soluble and / or water dispersible diluents may include, but are not limited to, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, sugars like dextrose, dextrans, dextrins, mannitol, sucrose, starches like pregelatinised starch, corn starch, maize starch , potato starch, rice starch and the like. In the present formulations, lactose is the most preferred diluent and is used in the compositions in an amount ranging from 5-30% by weight of the total composition more preferably from 7 to 27 % of the total weight of the composition. In addition to the above ingredients, pharmaceutically acceptable excipients like lubricants and /or glidants and /or anti adherants may be used to facilitate the process of compression. Examples of such excipients include talc, magnesium stearate, stearic acid, colloidal silicon dioxide, and such other excipients. In the present invention, magnesium stearate is used as the glidant at a concentration ranging from 0.2 to 2.0 % by weight of the total composition more preferably from 0.5 to 1.0 % of the composition. According to the process for preparation of pharmaceutical composition of the present invention, the active ingredient , the hydrophilic polymer and the water soluble diluent are mixed together thoroughly and granulated with either purified 8 water alone or preferably with a mixture of water and alcohol, preferably isopropyl alcohol (IPA), in the ratio 1:2 to 2:1 preferably 1:1. This granulation is then dried and sized. The resulting granulation may be blended with tablet lubricants and then compressed into tablets. A suitable mass mixer like horizontal mixer or more preferably an octagonal blender is used for blending the active ingredient, the hydrophilic polymer and the diluent and optimum mixing time may be 10 -20 minutes. The blended powder is then granulated using granulating liquid which may be purified water or IPA: water (1:1), mixing time 30 minutes - 1 hour. The blend is intermittently forcibly passed through a suitable mesh preferably sieve no 12 (IP) atleast twice to facilitate uniform distribution of binder liquid in the mass. The resulting advantage of such a process is that it enables the employment of minimum amount of water in the blend and hence ensures minimum exposure of the active ingredient drug to moisture at the same time yielding an optimum granulation. The resulting granules are first air dried and then dried at temperature 45°C - 55°C for 1-2 hours. Such a modification of the drying process ensures minimum exposure of the active ingredient drug to heat, thus preventing degradation of the active ingredient during processing. The granules are dried to an LOD (Loss on Drying) of 3.0 % to 5.0 % w/w. The dried granules are then sized to obtain granules of size 1.0 mm to 71 Op. The proportion of granules may be 20 % to 50 % by weight of the blend and that of fines from 50 -80 %. The advantage of such a granulation process is that it is a simple, convenient and eliminates the need for expensive equipment or skilled labour. The granulation process is optimized to ensure against degradation and subsequent loss of potency of drug during processing to affect stability of the final formulation. Upto 0-5% overages of the active ingredient may be included to counter losses. The resulting granules are then blended with tablet lubricant to form lubricated granules. The core tablets are obtained by compressing the lubricated blend using a rotary compression machine and they exhibit satisfactory physical parameters like low 9 friability and good hardness between 3-12 kg/sq. cm preferably 6-9 kg/sq. cm. The blend may be compressed to required shape and size of tablet, preferably circular or capsule shaped to facilitate the coating procedure. The tablets may be optionally coated with rapidly dissolving water soluble film coat; the polymer belonging to the group of low viscosity HPMC preferable Methocel E-5 manufactured by Dow chemicals, USA at a concentration of 1-5% of coating formula preferably 1- 3.0 % w/v of the coating formula. The core tablets are designed to be preferably circular or capsule shaped which ensures smooth rolling of the tablets in the coating pan thus leading to more uniform coating with negligible wearing of edges during rolling. The tablets may be coated to a weight build up of about 1 % to 5 % by weight preferably from about 1 % to 3 % by weight. The final tablets thus show low friability and good hardness between 5-12 kg/sq. cm. along with excellent physical and chemical stability. Other conventional tablet ingredients such as F D & C colors may be included in the present formulation from 0.01 % to 1.0 % by weight. jojE-what). These are included in the coating formula at the stage of coating of the core tablets. In the present Invention Lake Sunset yellow and Lake Tartrazine yellow are used as F D & C colors in combination of 1: 4 to get yellow to light orange colored coated tablets. In most preferred embodiment of the present invention, the pharmaceutical compositions comprises 50 to 90 % by weight of Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, more preferably from about 60 - 85 % by weight, and about 2 - 20 % of a low to medium viscosity grade Hydroxy Propyl Methyl Cellulose (HPMC), preferably from 5 - 8 % of HPMC having viscosity of 100 to 500 centipoise. The pharmaceutical compositions also comprises of 5-30 % by weight of one or more water soluble and / or water dispersible diluent, preferably lactose more preferably 7 - 27 % by weight of the total composition. 10 The most preferred process for preparing pharmaceutical formulations comprises mixing the active ingredient, hydrophilic polymer and water soluble or water dispersible diluent followed by wet granulation of the blend using a mixture of isopropyl alcohol and water in the ratio of 2:1 to 1:2 preferably in a ratio of 1:1. The blend is then intermittently passed through a suitable mesh preferably twice to facilitate uniform distribution of granulating fluid. The drying process is also optimized by air-drying first and then dried at temperature 45°C - 55°C for 1-2 hours to minimize exposure of the active ingredient drug to heat, thus preventing degradation of the active ingredient during processing. The granules are blended with a lubricant magnesium stearate 0.1 to 2.0 % of total composition preferably from 0.5 to 1.0 % and compressed to preferably circular or capsule shaped tablets having a hardness of 3-12 kg/sq. cm. preferably 6-9 kg/sq. cm. The tablets are preferably coated using rapidly dissolving water soluble film coat, the polymer belonging to the group of low viscosity HPMC preferably Methocel E-5 manufactured by Dow chemicals, USA at a concentration of 1-5 % w/v of coating formula preferably 1- 3.0 % w/v of the coating formula. The tablets may be coated to a weight build up of about 1 % to 5 % by weight preferably from about 1 % to 3 % by weight to give final tablets having hardness 5- 12 kg/sq cm. F D & C colors may be included in the present formulation from 0.01 % to 1.0 % by weight most preferably a combination of Lake Sunset yellow and Lake Tartrazine yellow in the ratio of 1:4 to get yellow to light orange colored coated tablets. In the second embodiment of the invention HPMC K50 (viscosity 50 centipoise) or HPMC K4M ( viscosity 4000 centipoise) may be used instead of HPMC K100 from 2 to 20 % by weight, preferably from 10 - 20 % for 50 centipoise and from 2-10 % for 4000 centipoise by weight of the total composition. The granulating fluid used may be a mixture of ethanol and purified water in the ratio 2:1 to 1:2, more preferably 1:1. In the third embodiment of the invention the granulating fluid used comprises of purified water only. 11 The modified release tablet formulation prepared according to the present invention is not a mere admixture but has properties different from the sum total of the properties of its individual ingredients. The present invention is illustrated by the following examples:- Example 1 The following example illustrates the manufacture of controlled release tablets of Cefadroxil having a composition as given in Table 1A having an eight hour release profile. Table 1A Ingredient mg/tab % by weight Cefadroxil monohydrate 1050 84.0 Lactose 90 7.20 Hydroxy propyl methyl cellulose(Metolose 90 SH 100) 100 8.00 Magnesium stearate 10 0.80 IPA : water ( 50 : 50) q.s. q.s. 1250 100 (q.s.: - quantity sufficient) The compression is carried out using capsule shaped punches of dimensions 20. lmm (length) and 9.1 mm (width) at a hardness of 8-10 kg/sq.cm. The core tablets are then coated with a non aqueous coating formula illustrated as follows :- Table IB Ingredients %w/w Hydroxy propyl methyl cellulose (Methocel E-5) 3.0 -Diethyl phthalate 0.45 PEG 4000 0.45 Talc 1.10 , Titanium dioxide 0.70 Methylene chloride 47.00 Methanol 47.00 Lake Tartrazine yellow 0.10 Lake Sunset yellow 0.025 12 Release profile of final coated tablets in 900 ml distilled water at 100 rpm using USP apparatus type 2 is as follows. The estimation of Cefadroxil was carried out at a wavelength of 263 nm (nm : nanometers). Time (in minutes) % released 0 0 60 mins. 23 120 mins 32 240 mins 68 360 mins 86 480 mins 99 Example 2 The following composition is again a controlled release Cefadroxil tablet showing a four hour release profile. Table 2 Ingredient mg/tab % by weight Cefadroxil monohydrate 525 67.30 Lactose 210 26.90 Hydroxy propyl methyl cellulose( Metolose 90 SH 100) 40 5.13 Magnesium stearate 5 0.64 IPA water q.s. q.s. 780 100 (q.s.: - quantity sufficient) The compression is carried out using circular punches to obtain circular tablets of diameter 12.0 mm having a hardness of 7-10 kg/sq.cm. The tablets are coated as per formula in example 1. Release profile of final coated tablets is as follows:- Time (in minutes ) % released 0 0 30min 20 60min 40 13 120 min 70 180 min 80 240 min 99 Example 3 The following composition is that of a controlled release Cephalexin tablet having a four hour release profile. Table 3 Ingredient mg/tab % by weight Cephalexin monohydrate 402.90 (overages:2%) 81.74 Lactose 50 10.14 Hydroxy propyl methyl cellulose(Metolose 90 SH 100) 35 7.10 Magnesium stearate 5 1.02 IPA : water (50:50) q.s. q.s. 492.9 mg 100 (q.s.: - quantity sufficient) The blend is compressed at parameters similar to example 2. Example 4 The following example is that of a Cephalexin controlled release tablet of higher strength. Table 4 Ingredient mg/tab % by weight Cephalexin monohydrate 805.8 (overages:2%) 82.00 Lactose 100 10.18 Hydroxy propyl methyl cellulose(Metolose 90 SH 100) 70 7.12 Magnesium stearate 7 0.71 IPA : water q.s. q.s. 982.8 mg 100 (q.s.: - quantity sufficient) 14 The core tablets are obtained employing parameters similar to example 1. Release profile of final coated tablets of both example 3 and example 4 are similar as illustrated below. The release profile of tablets obtained as per example 4 is compared against that obtained from a marketed product that is Phexin BD ® (manufactured by Ranbaxy Labs Ltd.) of strength 375 mg Cephalexin. The estimation of Cephalexin was carried out at a wavelength of 262 nm. Time (in minutes) % released Phexin BD ® (Ranbaxy Labs Ltd.) 0 0 0 30min 25 30 60min 46 48 120 min 77 80 180 min 90 95 240 min 99 101.0 Thus similar release pattern is obtained utilizing a simple granulation process and employing a low viscosity grade HPMC. , Example 5 The following composition for Cephalexin gives a 12 hour release profile. Table 5 Ingredient mg/tab % by weight Cephalexin monohydrate 805.8 (overages:2%) 78.4 Lactose 100 9.73 Hydroxy propyl methyl cellulose (Metolose 90 SH 100) 115 11.19 Magnesium stearate 7 0.68 IPA: water q.s. q.s. 1027.8 mg 100 .(q.s.: - quantity sufficient) 15 The core tablets are obtained employing parameters similar to example l.The compression is carried out using capsule shaped punches of dimensions 20.1 mm (length) and 9.1 mm (width) at a hardness of 8-10 kg/sq.cm. Release profile of final coated tablets is as given below: - Time (in minutes) % released 0 0 60min 17 120 min 35 240min 47 480 min 84 720 min 100 The reader will see that the present invention boasts of present formulation and process alternative compared to prior art. The advantages of the present invention are manifold and range from simplicity of processing and greater stability of formulation to more cost effectiveness. To summarize, our invention effectively utilizes a low viscosity HPMC to achieve controlled release profile for Cefadroxil or Cephalexin or their pharmaceutically acceptable hydrates, salts or esters thereof. The modified release pharmaceutical formulations and process of their preparation eliminate the use of additional expensive excipients as well as expensive equipment. The granulation process, in addition to being a simpler and a less expensive alternative to prior art is also optimized to ensure minimum exposure of the active ingredient drug to heat preventing degradation and to ensure maximum stability of active ingredient during processing. The final product thus is more cost effective and provides a consistent controlled release pattern, thus reducing frequency of dosing and thus improving patient compliance to therapy. While the above description describes many specificities, these should not be construed as limitations in the scope of the invention, but rather as an exemplification of one preferred embodiment thereof. Many other variations are possible, for example: 16 Other Cephalosporin antibiotics like Cefaclor and Cephradine etc. may be used. HPMC K50 (viscosity 50 centipoise) or HPMC K4M (viscosity 4000 centipoise) may be used instead of HPMC K100 from 2 to 20 % by weight, preferably from 10 - 20 % for 50 centipoise and from 5-10 % for 4000 centipoise by weight of the total composition. Secondly, the granulating fluid used may be a mixture of ethanol and purified water in the ratio 2:1 to 1:2, more preferably 1:1. Thirdly, purified water alone may be used as the granulating fluid. Dr. Gopakumar G. Nair Agent for the Applicant Gopakumar Nair Associates Dated this 8th day of July 2003 We claim, 1. A modified release pharmaceutical compositions in the form of a tablet coated with a water soluble polymeric film comprising cefadroxil, or cephalexin or their pharmaceutically acceptable hydrates, salts or esters as an active ingredient in an amount ranging from 50% to 90%, a hydrophilic polymer hydroxy propyl methyl cellulose (HPMC) in an amount ranging from 2- 20 %, more preferably from 5 % to 8 % by weight of the total composition and a water soluble or water dispersible diluent. 2. Pharmaceutical compositions as described herein with reference to the preceding claims and foregoing examples 1 to 5. Dr. Gopakumar G. Nair Agent for the Applicant Gopakumar Nair Associates Dated this 8th day of July, 2003

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652-mum-2002-petition under rule 137(7-4-2004).pdf